(Pyrimidinyl) (phenyl) substituted fused heteroaryl p38 inhibiting and PKG kinase inhibiting compounds

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts thereof are useful in the treatment of cytokine mediated diseases such as arthritis and in the treatment and/or prevention of protozoal diseases such as coccidiosis

RELATED APPLICATION DATA

This is a National filing under 35 USC 371 of PCT/US 02/19507, filedJun. 21, 2002, which claims priority from U.S. Ser. No. 60/300,748,filed Jun. 25, 2001.

BACKGROUND OF THE INVENTION

The present invention relates to (pyrimidyl)(phenyl)substituted fusedheteroaryl compounds which have cytokine inhibitory activity. Thepresent invention also relates to (pyrimidyl)(phenyl)substituted fusedheteroaryl compounds which have cGMP dependent protein kinase (“PKG”)inhibitory activity.

Cytokine mediated diseases and cytokine inhibition, suppression andantagonism are used in the context of diseases or conditions in whichexcessive or unregulated production or activity of one or more cytokinesoccurs. Examples of cytokines which are effected typically includeInterleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8) andTumor Necrosis Factor (TNF).

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are produced by avariety of cells that are involved in immunoregulation and otherphysiological conditions.

There are many disease states in which IL-1 is implicated. Examples arerheumatoid arthritis, osteoarthritis, endotoxemia, toxic shock syndrome,acute and chronic inflammatory diseases, such as the inflammatoryreaction induced by endotoxin or inflammatory bowel disease;tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriaticarthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumaticarthritis, rubella arthritis and acute synovitis. Recent evidence alsolinks IL-1 activity to diabetes.

Interleukin-1 has been demonstrated to mediate a variety of biologicalactivities thought to be important in immunoregulation and otherphysiological conditions. [See, e.g., Dinarello et al., Rev. Infect.Disease, 6, 51 (1984)]. The known biological activities of IL-1 includethe activation of T helper cells, induction of fever, stimulation ofprostaglandin or collagenase production, neutrophil chemotaxis,induction of acute phase proteins and the suppression of plasma ironlevels.

Excessive or unregulated tumor necrosis factor (TNF) production oractivity has been implicated in mediating or exacerbating rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, andother arthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcosis, bone resorption diseases, reperfusioninjury, graft v. host rejection, allograft rejections, fever and myalgiadue to infection, cachexia secondary to infection or malignancy,cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDSrelated complex (ARC), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis and pyresis.

Monokines, such as TNF, have also been shown to activate HIV replicationin monocytes and/or macrophages [See Poli, et al., Proc. Natl. Acad.Sci., 87:782–784 (1990)], therefore, inhibition of monokine productionor activity aids in limiting HIV progression. TNF has been implicated invarious roles with other viral infections, such as the cytomegalovirus(CMV), influenza virus and the herpes virus.

Interleukin-6 (IL-6) is a cytokine effecting the immune system andhematopoiesis. It is produced by several mammalian cell types inresponse to agents such as IL-1, and is correlated with disease statessuch as angiofollicular lymphoid hyperplasia.

Interleukin-8 (IL-8) is a chemotactic factor first identified andcharacterized in 1987. Many different names have been applied to IL-8,such as neutrophil attractant/activation protein-1 (NAP-1), monocytederived neutrophil chemotactic factor (MDNCF), neutrophil activatingfactor (NAF), and T-cell lymphocyte chemotactic factor. Like IL-1, IL-8is produced by several cell types, including mononuclear cells,fibroblasts, endothelial cells and ketainocytes. Its production isinduced by IL-1, TNF and by lipopolysaccharide (LPS). IL-8 stimulates anumber of cellular functions in vitro. It is a chemoattractant forneutrophils, T-lymphocytes and basophils. It induces histamine releasefrom basophils. It causes lysozomal enzyme release and respiratory burstfrom neutrophils, and it has been shown to increase the surfaceexpression of Mac-1 (CD11b/CD 18) on neutrophils without de novo proteinsynthesis.

There remains a need for compounds which are useful in treating cytokinemediated diseases, and as such, inhibit, suppress or antagonize theproduction or activity of cytokines such as IL-1, IL-6, IL-8 and TNF.

Parasitic protozoa are responsible for a wide variety of infections inman and animals. Many of the diseases are life threatening to the host,and in animal husbandry, can cause considerable economic loss. Forexample, malaria remains a significant health threat to humans despitemassive international attempts to eradicate the disease; trypanosomiasissuch as Chagas disease caused by Trypanosoma cruzi and African sleepingsickness caused by T. brucei are not uncommon in South America andAfrica, respectively; and opportunistic infections in immuno-compromisedhosts caused by Pneumocystis carinii, Toxoplasma gondii, Cryptosporidiumsp. are becoming increasingly significant in the developed countries.

Coccidiosis, a widespread disease of domesticated animals, is caused byprotozoal infection. In the poultry industry, coccidiosis is responsiblefor high levels of morbidity and mortality in the bird population andmay result in extreme economic losses. The infectious agents areprotozoa of the genus Eimeria. Some of the most significant avianEimeria species include E. tenella, E. acervulina, E. necatrix, E.brunetti and E. maxima.

In some protozoal diseases, such as Chagas disease, there is nosatisfactory treatment; in others, drug-resistant strains of theprotozoa may develop. A biochemical target of antiprotozoal drugs, cGMPdependent protein kinases (PKG), has been identified, the inhibition ofwhich effectively treats protozoal infections such as coccidiosis andChagas disease.

cGMP dependent protein kinases catalyze the phosphorylation of specificprotein substrates. In the absence of cGMP the activity of these enzymesis very low. Thus, the inhibition of such PKG kinases can be lethal tothe organism. There is a need for compounds that treat (or prevent by asubtherapeutic prophalactic dosing) coccidiosis, Chagas disease, andtoxoplasmosis. Compounds that inhibit the PKG kinase of the infectingprotozoa can be such preventive and treating compounds. Importantly,compounds that selectively inhibit the PKG kinase of the infectingprotozoa without inhibiting the PKG kinase of mammalian PKG kinase wouldbe lethal to protozoa while being safe for mammals. Accordingly, thereis a need for such selective compounds for the treatment of protozoalinfections such as coccidiosis, Chagas disease, and toxoplasmosis.

International Patent Publication Nos. WO 99/51233, WO 99/51232, WO97/21704, WO 97/21703, and WO 00/04013 describe fused heteroarylcompounds that are antagonists of gonadotropin releasing hormone.International Patent Publication No. WO 96/06840 describes diarylbicyclic heterocycles as inhibitors of cyclooxygenase-2.

International Patent Publication No. WO 98/22457 describes aryl andheteroaryl substituted fused pyrrole antiinflammatory agents.International Patent Publication No. WO 01/22965 describes substitutedimidazoles having cytokine inhibitory activity. International PatentPublication No. WO 01/34605 describes substituted2-aryl-3-(heteroaryl)-imidazo[1,2-a]primidines. International PatentPublication No. WO 01/30778 describes tiazole and imidazo[4,5-b]pyridinecompounds. International Patent Publication No. WO 00/63204 describessubstituted azoles.

The compounds3-(2-Methylsulfanylpyrimidin-4-yl)-2-(3-trifluoromethylphenyl)imidazo[1,2-a]-pyrimidine:

and3-(2-Methylsulfonylpyrimidin-4-yl)-2-(3-trifluoromethylphenyl)imidazo[1,2-a]-pyrimidine:

were described in International Patent Publication No. WO 01/22965 asintermediates in a process to make a substituted imidazole.

SUMMARY OF THE INVENTION

The present invention relates to compound I of the formula

wherein FusedHet is

or a pharmaceutically acceptable salt and/or hydrate thereof, or whereapplicable, a geometric or optical isomer or racemic mixture thereof.

This invention also relates to a pharmaceutical composition that iscomprised of a compound of formula I as defined above in combinationwith a pharmaceutically acceptable carrier.

Also included in the invention is a method of treating a cytokinemediated disease in a mammal, comprising administering to a mammalianpatient in need of such treatment an amount of a compound of formula Iwhich is effective to treat the cytokine mediated disease.

The invention includes a method of treating a protozoal disease in amammel or bird, comprising administering to a mammalian or avian patientin need of such treatment an amount of a compound of formula I which iseffective to treat the protozoal disease. Further, the inventionincludes a method of preventing a protozoal disease in a mammel or bird,comprising administering to a mammalian or avian patient in need of suchtreatment a prophalactic amount of a compound of formula I which iseffective to prevent the protozoal disease.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds represented by formula (I):

or a pharmaceutically acceptable salt or hydrate thereof,

-   -   wherein FusedHet is

-   -   R¹ is H,        -   —C₁₋₆alkyl,        -   —C(O)(C₁₋₆alkyl),        -   —C(O)—C₁₋₆alkyl-aryl,        -   —C₀₋₄alkyl-aryl,        -   —C₀₋₄alkyl-indanyl,        -   —C₀₋₄alkyl-imidazolyl,        -   —C₀₋₄alkyl-thiazolyl,        -   —C₀₋₄alkyl-pyrazolyl,        -   —C₀₋₄alkyl-oxadiazolyl,        -   —C₀₋₄alkyl-C₃₋₆cycloalkyl,        -   —C₀₋₄alkyl-C₁₋₄alkoxy,        -   —C₁₋₄alkyl-N(C₀₋₄alkyl)(—C₀₋₄alkyl),        -   —C₁₋₄alkyl-N(—C₀₋₄alkyl)—CO—C₁₋₄alkoxy,        -   —C₁₋₄alkyl-piperadinyl,        -   —C₀₋₄alkyl-triazolyl,        -   —C₁₋₄alkyl-imidazothiazolyl,        -   —C₁₋₄alkyl-benzimidazolyl,        -   —C₁₋₄alkyl-benzothiazolyl,        -   —C₁₋₄alkyl-benzotetrahydrofuranyl,        -   —C₁₋₄alkyl-benzodioxolyl,        -   —C₁₋₄alkyl-(heterocycloC₄O₂alkyl),        -   —C₁₋₄alkyl-(heterocycloC₅O₁alkyl),        -   —C₁₋₄alkyl-tetrahydrofuran, or        -   —C₁₋₄alkyl-oxetanyl;    -   R¹¹ is H or —C₁₋₆alkyl;    -   or R¹ and R¹¹, together with the N to which they are attached,        form a morpholinyl;    -   R², R²¹, R²² each independently is H, halogen, or —C₁₋₄alkyl;    -   R³ is H,        -   —C₁₋₄alkyl,        -   —C₃₋₆cycloalkyl,        -   —C₁₋₄alkyl-aryl,        -   —C₁₋₄alkyl-azetidinyl,        -   —C₁₋₄alkyl-azetidinyl-CO—C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),        -   —C₁₋₄alkyl-pyrrolidinyl,        -   —C₁₋₄alkyl-piperidinyl,        -   —C₁₋₄alkyl-morpholinyl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl-C₁₋₄alkoxy),        -   —C₀₋₄alkyl-N(C₀₋₄alkyl-C₁₋₄alkoxy)(C₀₋₄alkyl-C₁₋₄alkoxy),        -   —C₁₋₄alkyl-N(C₀₋₄alkyl)(C₁₋₄alkyl)-aryl,        -   —C₁₋₄alkyl-N(C₀₋₄alkyl)—C₁₋₄alkyl-tetrahydrofuranyl,        -   —C₁₋₄alkyl-N(C₀₋₄alkyl)—C₁₋₄alkyl-azetidinyl,        -   —C₁₋₄alkyl-N(C₀₋₄alkyl)—C₁₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),        -   —C₁₋₄alkyl-N(C₀₋₄alkyl)—C₁₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-SO₂C₁₋₄alkyl),        -   —CO—N(C₀₋₄alkyl)—C₁₋₄alkyl-aryl,        -   —CO—N(C₀₋₄alkyl)—C₁₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),        -   —C₀₋₄alkyl-CO—C₀₋₄alkyl,        -   —C₀₋₄alkyl-CO—C₀₋₄alkoxy,        -   —C₀₋₄alkyl-CO—N(C₀₋₄alkyl)—C₁₋₄alkyl-C₁₋₄alkoxy,        -   —C₀₋₄alkyl-CO—N(C₀₋₄alkyl)—C₁₋₄alkyl-aryl,        -   —C₀₋₄alkyl-CO-piperidinyl,        -   —C₁₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),        -   —C₀₋₄alkyl-CO—C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),        -   —O—C₁₋₄alkyl-aryl,        -   —C₁₋₄alkyl-O—C₁₋₄alkyl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkoxy,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-aryl,        -   —CO-alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl(aryl)₂,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-pyrrolyl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-pyrrolidinyl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-azetidinyl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₂₋₄alkenyl-pyrrolidinyl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-thiophenyl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₂₋₄alkenyl-thiophenyl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—S—C₁₋₄alkyl-aryl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₃₋₆cyclolkyl,        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—O—C₁₋₄alkyl-aryl,        -   —C₀₋₄alkyl-CO—N(C₀₋₄alkyl)—C₀₋₄alkyl-C₁₋₄alkoxy,        -   —C₁₋₄alkyl-N(C₀₋₄alkyl)(—SO₂C₁₋₄alkyl),        -   —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₁₋₄alkyl-SO₂C₁₋₄alkyl,        -   —C₀₋₄alkyl-S—C₁₋₄alkyl-aryl,        -   —C₁₋₄alkyl-PO(C₁₋₄alkoxy)(C₁₋₄alkoxy),        -   —C₁₋₄alkyl-azetidinyl-CO—N(C₀₋₄alkyl)(C₀₋₄alkyl),        -   —C₁₋₄alkyl-(heterocycloC₄N₁O₁alkyl),        -   —C₀₋₄alkyl-CO—(heterocycloC₅N₁alkyl),        -   —C₀₋₄alkyl-CO—N(C₀₋₄alkyl)-(heterocycloC₅N₁alkyl),        -   —C₁₋₄alkyl-(heterocycloC₄N₂alkyl)—C₁₋₄alkyl,        -   —C₁₋₄alkyl-(heterocycloC₄N₂alkyl)—CO—C₀₋₄alkoxy,        -   —C₁₋₄alkyl-(heterocycloC₄N₂alkyl)—C₁₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),        -   —C₁₋₄alkyl-(heterobicycloC₅N₂alkyl)—C₁₋₄alkyl, or        -   —C₁₋₄alkyl-NH—(heterobicycloC₇N₁alkyl); and    -   R⁴ is —C₁₋₆alkyl;    -   wherein any of the above aryl, hetaryl, cycloalkyl, or        heterocycloalkyl optionally may be substituted with 1–4        substituents, each substituent independently is halogen, NO₂,        —CN, —C₁₋₄alkyl, —C₀₋₄alkoxy, —S—C₁₋₄alkyl, or        —C₀₋₄alkyl-(CO)—C₀₋₄alkoxy; and any of the above alkyl        optionally may be substituted with 1–4 substituents, each        substituent independently is halogen, —N₃, —CN, —COOH, or        —C₀₋₄alkoxy.

This invention also includes a binary compound formed from two compoundsof formula (I), as described above, connected together by linking therespective R3 groups of each compound. In one aspect the binary compoundis a dimer of two identical compounds of formula (I), as describedabove.

In one aspect, the compound of this invention is represented by formula(I), or a pharmaceutically acceptable salt or hydrate thereof, whereinFusedHet is

In a second aspect, the compound of this invention is represented byformula (I), or a pharmaceutically acceptable salt or hydrate thereof,wherein FusedHet is

In a third aspect, the compound of this invention is represented byformula (I), or a pharmaceutically acceptable salt or hydrate thereof,wherein FusedHet is

In a fourth aspect, the compound of this invention is represented byformula (I), or a pharmaceutically acceptable salt or hydrate thereof,wherein FusedHet is

In a fifth aspect, the compound of this invention is represented byformula (I), or a pharmaceutically acceptable salt or hydrate thereof,wherein FusedHet is

In a sixth aspect, the compound of this invention is represented byformula (I), or a pharmaceutically acceptable salt or hydrate thereof,wherein FusedHet is

In a seventh aspect, the compound of this invention is represented byformula (I), or a pharmaceutically acceptable salt or hydrate thereof,wherein FusedHet is

In an eighth aspect, the compound of this invention is represented byformula (I), or a pharmaceutically acceptable salt or hydrate thereof,wherein FusedHet is

In a ninth aspect, the compound of this invention is represented byformula (I), or a pharmaceutically acceptable salt or hydrate thereof,wherein FusedHet is

In a tenth aspect, the compound of this invention is represented byformula (I), or a pharmaceutically acceptable salt or hydrate thereof,wherein FusedHet is

This invention also relates to a pharmaceutical composition that iscomprised of a compound of formula (I) as defined above in combinationwith a pharmaceutically acceptable carrier.

Also included in the invention is a method of treating a cytokinemediated disease in a mammal, comprising administering to a mammalianpatient in need of such treatment an amount of a compound of formula(I), which is effective to treat the cytokine mediated disease.

The invention includes a method of treating a protozoal disease in amammel, comprising administering to a mammalian patient in need of suchtreatment an amount of a compound of formula (I), which is effective totreat the protozoal disease. Further, the invention includes a method ofpreventing a protozoal disease in a mammel, comprising administering toa mammalian patient in need of such treatment a prophalactic amount of acompound of formula (I), which is effective to prevent the protozoaldisease.

Unless otherwise stated or indicated, the following definitions shallapply throughout the specification and claims.

As used herein, “alkyl” as well as other groups having the prefix “alk”such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like,means carbon chains which may be linear or branched or combinationsthereof. Examples of alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and thelike. “Alkenyl”, “alkynyl” and other like terms include carbon chainscontaining at least one unsaturated C—C bond.

The term “cycloalkyl” means carbocycles containing no heteroatoms, andincludes mono-, bi- and tricyclic saturated carbocycles, as well asfused ring systems. Such fused ring systems can include one ring that ispartially or fully unsaturated such as a benzene ring to form fused ringsystems such as benzofused carbocycles. Cycloalkyl includes such fusedring systems as spirofused ring systems. Examples of cycloalkyl includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene,adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphalene andthe like. Similarly, “cycloalkenyl” means carbocycles containing noheteroatoms and at least one non-aromatic C—C double bond, and includemono-, bi- and tricyclic partially saturated carbocycles, as well asbenzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl,indenyl, and the like.

The term “aryl” means an aromatic subsituent which is a single ring ormultiple rings fused together. When formed of multiple rings, at leastone of the constituent rings is aromatic. The preferred arylsubstituents are phenyl and napthyl groups.

The term “cycloalkyloxy” unless specifically stated otherwise includes acycloalkyl group connected by a short C₁–C₂alkyl length to the oxyconnecting atom.

The term “C₀–C₆alkyl” includes alkyls containing 6, 5, 4, 3, 2, 1, or nocarbon atoms. A terminal alkyl with no carbon atoms is a hydrogen atom.A bridging alkyl with no carbon atoms is a direct bond. It is understoodthat, for the purposes of substitution, an alkyl with no carbon atomshas no substituents and takes no substitution. The term “—C₀₋₄alkoxy” is—OH for —C₀alkoxy.

The term “hetero” unless specifically stated otherwise includes one ormore O, S, or N atoms. For example, heterocycloalkyl (“heterocycle”) andheteroaryl include ring systems that contain one or more O, S, or Natoms in the ring, including mixtures of such atoms. The hetero atomsreplace ring carbon atoms. Thus, for example, a heterocycloC₅alkyl is afive member ring containing from 5 to no carbon atoms. However, theheteroatoms can be specified. Thus, a heterocycloC₄N₁O₁alkyl is a sixmember saturated ring containing 4 carbon atoms, 1 nitrogen atom, and 1oxygen atom. Similar notation is used for heterobicycloclkyls.

Generally, unless otherwise stated, “heterocycle” is a 3- to 7-memberednon-aromatic ring containing 1–4 heteroatoms selected from N, O andS(O)m, which may be optionally fused to a benzene ring, and in which upto three additional carbon atoms may be replaced by said heteroatoms.When three heteroatoms are present in the heterocycle, they are not alllinked together. Examples of heterocycle include oxiranyl, aziridinyl,azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothienyl including sulfoxide and sulfones thereof, 2,3- and2,5-dihydrofuranyl, 1,3-dioxanyl, 1,3-dioxolanyl, pyrrolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, benzoxazinyl, 2,3-dihydrobenzofuranyl1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl.,

“Heteroaryl” is a mono-or bicyclic aromatic ring containing from 1 to 6heteroatoms independently selected from N, O and S wherein each ring hasfive or six ring atoms. Examples of heteroaryl include pyridyl,pyrimidinyl, pyrrolyl, furyl, thienyl, imidazolyl, thiazolyl,thiadiazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxazolyl,imidazolidinyl, pyrazolyl, isoxazolyl, benzothiadiazolyl, indolyl,indolinyl, benzodioxolyl, benzodioxanyl, benzothiophenyl, benzofuranyl,benzimidazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl,benzotriazolyl, benzoxazolyl, purinyl, furopyridine and thienopyridine.

The term “amine” unless specifically stated otherwise includes primary,secondary and tertiary amines.

The term “halogen” or “halo” is intended to include fluorine, chlorine,bromine and iodine.

The term “optionally substituted” is intended to include bothsubstituted and unsubstituted. Thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring. Further,optionally substituted multiple moieties such as, for example, alkylarylare intended to mean that the aryl and the aryl groups are optionallysubstituted. If only one of the multiple moieties is optionallysubstituted then it will be specifically recited such as “an alkylaryl,the aryl optionally substituted with halogen or hydroxyl.”

The term “composition”, as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

Compounds described herein contain one or more double bonds and may thusgive rise to cis/trans isomers as well as other conformational isomers.The present invention includes all such possible isomers as well asmixtures of such isomers.

Compounds described herein can contain one or more asymmetric centersand may thus give rise to diastereomers and optical isomers. The presentinvention includes all such possible diastereomers as well as theirracemic mixtures, their substantially purse resolved enantiomers, allpossible geometric isomers, and pharmaceutically acceptable saltsthereof. The above Formula I is shown without a definitivestereochemistry at certain positions. The present invention includes allstereoisomers of Formula I and pharmaceutically acceptable saltsthereof. Further, mixtures of stereoisomers as well as isolated specificstereoisomers are also included. During the course of the syntheticprocedures used to prepare such compounds, or in using racemization orepimerization procedures known to those skilled in the art, the productsof such procedures can be a mixture of stereoisomers.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Particularly preferred arethe ammonium, calcium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, as well as cyclicamines and substituted amines such as naturally occurring andsynthesized substituted amines. Other pharmaceutically acceptableorganic non-toxic bases from which salts can be formed include ionexchange resins such as, for example, arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.Particularly preferred are citric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The compounds of the present invention may have chiral centers otherthan those centers whose stereochemistry is depicted in formula I, andtherefore may occur as racemates, racemic mixtures and as individualenantiomers or diastereomers, with all such isomeric forms beingincluded in the present invention as well as mixtures thereof.Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

The term “TNF mediated disease or disease state” refers to diseasestates in which TNF plays a role, either by production or increasedactivity levels of TNF itself, or by causing another cytokine to bereleased, such as but not limited to IL-1 or IL-6. A disease state inwhich IL-1, for instance is a major component, and whose production oraction, is exacerbated or secreted in response to TNF, would thereforebe considered a disease state mediated by TNF.

The term “cytokine” as used herein means any secreted polypeptide thataffects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines regardless of which cells produce them. Examples ofcytokines include, but are not limited to, Interleukin-1 (IL-1),Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha(TNF-α) and Tumor Necrosis Factor-beta (TNF-β).

By the term “cytokine interfering or cytokine suppresive amount” ismeant an effective amount of a compound of formula I which will cause adecrease in the in vivo activity or level of the cytokine to normal orsub-normal levels, when given to the patient for the prophylaxis ortherapeutic treatment of a disease state which is exacerbated by, orcaused by, excessive or unregulated cytokine production or activity.

The compounds of formula I can be used in the prophylactic ortherapeutic treatment of disease states in mammals which are exacerbatedor caused by excessive or unregulated cytokines, e.g., IL-1, IL-6, IL-8or TNF.

Because the compounds of formula I inhibit cytokines, the compounds areuseful for treating diseases in which cytokine presence or activity isimplicated, such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions.

The compounds of formula I are useful to treat disease states mediatedby excessive or unregulated TNF production or activity. Such diseasesinclude, but are not limited to sepsis, septic shock, endotoxic shock,gram negative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoidosis, bone resorption diseases, such asosteoporosis, reperfusion injury, graft v. host rejection, allograftrejection, fever, myalgia due to infection, cachexia secondary toinfection or malignancy, cachexia secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDs related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,pyresis, AIDS and other viral infections, such as cytomegalovirus (CMV),influenza virus, and the herpes family of viruses such as Herpes Zosteror Simplex I and II.

The compounds of formula I are also useful topically in the treatment ofinflammation such as in the treatment of rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions; inflamed joints, eczema, psoriasis or otherinflammatory skin conditions such as sunburn; inflammatory eyeconditions including conjunctivitis; pyresis, pain and other conditionsassociated with inflammation.

The compounds of formula I are also useful in treating diseasescharacterized by excessive IL-8 activity. These disease states includepsoriasis, inflammatory bowel disease, asthma, cardiac and renalreperfusion injury, adult respiratory distress syndrome, thrombosis andglomerulonephritis.

The invention thus includes a method of treating psoriasis, inflammatorybowel disease, asthma, cardiac and renal reperfusion injury, adultrespiratory distress syndrome, thrombosis and glomerulonephritis, in amammal in need of such treatment, which comprises administering to saidmammal a compound of formula I in an amount which is effective fortreating said disease or condition.

When administered to a patient for the treatment of a disease in which acytokine or cytokines are implicated, the dosage used can be variedwithin wide limits, depending upon the type of disease, the age andgeneral condition of the patient, the particular compound administered,the presence or level of toxicity or adverse effects experienced withthe drug and other factors. A representative example of a suitabledosage range is from as low as about 0.01 mg/kg to as high as about 100mg/kg. However, the dosage administered is generally left to thediscretion of the physician.

The methods of treatment can be carried out by delivering the compoundof formula I parenterally. The term ‘parenteral’ as used herein includesintravenous, intramuscular, or intraperitoneal administration. Thesubcutaneous and intramuscular forms of parenteral administration aregenerally preferred. The instant invention can also be carried out bydelivering the compound of formula I through subcutaneous, intranasal,intrarectal, transdermal or intravaginal routes.

The compounds of formula I may also be administered by inhalation. By‘inhalation’ is meant intranasal and oral inhalation administration.Appropriate dosage forms for such administration, such as an aerosolformulation or a metered dose inhaler, may be prepared by conventiontechniques.

The invention also relates to a pharmaceutical composition comprising acompound of formula I and a pharmaceutically acceptable carrier. Thecompounds of formula I may also be included in pharmaceuticalcompositions in combination with a second therapeutically activecompound.

The pharmaceutical carrier employed may be, for example, either a solid,liquid or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Examples of liquid carriers are syrup, peanutoil, olive oil, water and the like. Examples of gaseous carriers includecarbon dioxide and nitrogen.

Similarly, the carrier or diluent may include time delay material wellknown in the art, such as glyceryl monostearate or glyceryl distearate,alone or with a wax.

A wide variety of pharmaceutical dosage forms can be employed. If asolid dosage is used for oral administration, the preparation can be inthe form of a tablet, hard gelatin capsule, troche or lozenge. Theamount of solid carrier will vary widely, but generally the amount ofthe present compound will be from about 0.025 mg to about 1 g with theamount of solid carrier making up the difference to the desired tablet,hard gelatin capsule, troche or lozenge size. Thus, the tablet, hardgelatin capsule, troche or lozenge conveniently would have, for example,0.025 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25 mg, 100 mg, 250mg, 500 mg, or 1000 mg of the present compound. The tablet, hard gelatincapsule, troche or lozenge is given conveniently once, twice or threetimes daily.

When a liquid dosage form is desired for oral administration, thepreparation is typically in the form of a syrup, emulsion, soft gelatincapsule, suspension or solution. When a parenteral dosage form is to beemployed, the drug may be in solid or liquid form, and may be formulatedfor administration directly or may be suitable for reconstitution.

Topical dosage forms are also included. Examples of topical dosage formsare solids, liquids and semi-solids. Solids would include dustingpowders, poultices and the like. Liquids include solutions, suspensionsand emulsions. Semi-solids include creams, ointments, gels and the like.

The amount of a compound of formula I used topically will, of course,vary with the compound chosen, the nature and severity of the condition,and can be varied in accordance with the discretion of the physician. Arepresentative, topical, dose of a compound of formula I is from as lowas about 0.01 mg to as high as about 2.0 g, administered one to four,preferably one to two times daily.

The active ingredient may comprise, for topical administration,conveniently from about 0.001% to about 10% w/w.

Drops according to the present invention may comprise sterile ornon-sterile aqueous or oil solutions or suspensions, and may be preparedby dissolving the active ingredient in a suitable aqueous solution,optionally including a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and optionally including a surface activeagent. The resulting solution may then be clarified by filtration,transferred to a suitable container which is then sealed and sterilizedby autoclaving or maintaining at 98–100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container aseptically. Examples of bactericidal andfungicidal agents suitable for inclusion in the drops arephenyl-mercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous liquid, with a greasy or non-greasy base. Thebase may comprise hydrocarbons such as hard, soft or liquid paraffin,glycerol, beeswax, a metallic soap; a mucilage; an oil of natural originsuch as almond, corn, arachis, castor or olive oil; wool fat or itsderivatives, or a fatty acid such as stearic or oleic acid together withan alcohol such as propylene glycol or macrogels. The formulation mayincorporate any suitable surface active agent such as an anionic,cationic or non-ionic surfactant such as sorbitan esters orpolyoxyethylene derivatives thereof. Suspending agents such as naturalgums, cellulose derivatives or inorganic materials such as silicas, andother ingredients such as lanolin may also be included.

The ability of compounds of the present invention to inhibit thesynthesis or the activity of cytokines can be demonstrated using thefollowing in vitro assays.

Biological Assays

Lipopolysaccharide Mediated Production of Cytokines

Human peripheral blood mononuclear cells (PBMC) are isolated from freshhuman blood according to the procedure of Chin and Kostura, J. Immunol.,151:5574–5585(1993). Whole blood is collected by sterile venipunctureinto 60 mL syringes coated with 1.0 mL of sodium-heparin (Upjohn, 1000μ/mL) and diluted 1:1 in Hanks Balanced Salt Solution (Gibco). Theerythrocytes are separated from the PBMC's by centrifugation on aFicoll-Hypaque lymphocyte separation media. The PBMC's are washed threetimes in Hanks Balanced Salt Solution and then resuspended to a finalconcentration of 2×10⁶ cell/mL in RPMI containing 10% fresh autologoushuman serum, penicillin streptomycin (10/mL) and 0.05% DMSO.Lipopolysaccharide (Salmonella type Re545; Sigma Chemicals) is added tothe cells to a final concentration of 100 ng/mL. An aliquot (0.1 mL) ofthe cells is quickly dispensed into each well of a 96 well platecontaining 0.1 mL of the test compound, at the appropriate dilution, andare incubated for 24 hours at 37° C. in 5% CO₂. At the end of theculture period, cell culture supernatants are assayed for IL-1β, TNF-α,IL-6 and PGE2 production using specific ELISA.

IL-1 Mediated Cytokine Production

Human peripheral blood mononuclear cells are isolated from fresh humanblood according to the procedure of Chin and Kostura, J. Immunol.,151:5574–5585(1993). Whole blood is collected by sterile venipunctureinto 60 mL syringes coated with 1.0 mL of sodium-heparin (Upjohn, 1000μ/mL) and diluted 1:1 in Hanks Balanced Salt Solution (Gibco). Theerythrocytes are separated from the PBMC's by centrifugation on aFicoll-Hypaque lymphocyte separation media. The PBMC's are washed threetimes in Hanks Balanced Salt Solution and then resuspended to a finalconcentration of 2×10⁶ cell/mL in RPMI containing 10% fresh autologoushuman serum, penicillin streptomycin (10 μ/mL) and 0.05% DMSO. Endotoxinfree recombinant human IL-1b is then added to a final concentration of50 pMolar. An aliquot (0.1 mL) of the cells is quickly dispensed intoeach well of a 96 well plate containing 0.1 mL of the compound at theappropriate dilution and incubated for 24 hours at 37° C. in 5% CO₂. Atthe end of the culture period, cell culture supernatants are assayed forTNF-a, IL-6 and PGE2 synthesis using specific ELISA.

Determination of IL-1β, TNF-α, IL-6 and Prostanoid

Production from LPS or IL-1 Stimulated PBMC's

IL-1β ELISA

Human IL-1β can be detected in cell-culture supernatants or whole bloodwith the following specific trapping ELISA. 96 well plastic plates(Immulon 4; Dynatech) are coated for 12 hours at 4° C. with 1 mg/mLprotein-A affinity chromatography purified mouse anti-human IL-1βmonoclonal antibody (purchased as an ascites preparation from LAOEnterprise, Gaithersburg Md.) diluted in Dulbecco's phosphate-bufferedsaline (—MgCl₂, —CaCl₂). The plates are washed with PBS-Tween(Kirkegaard and Perry) then blocked with 1% BSA diluent and blockingsolution (Kirkegaard and Perry) for 60 minutes at room temperaturefollowed by washing with PBS Tween. IL-1β standards are prepared frompurified recombinant IL-1β produced from E. coli. The highestconcentration begins at 10 ng/mL followed by 11 two-fold serialdilutions. For detection of IL-1β from cell culture supernatants orblood plasma, 10–25 mL of supernatant is added to each test well with75–90 mL of PBS Tween. Samples are incubated at room temperature for 2hours then washed 6 times with PBS Tween on an automated plate washer(Dennly). Rabbit anti-human IL-1β polyclonal antisera diluted 1:500 inPBS-Tween is added to the plate and incubated for 1 hour at roomtemperature followed by six washes with PBS-Tween. Detection of boundrabbit anti-IL-1β IgG is accomplished with Fab′ fragments of Goatanti-rabbit IgG-horseradish peroxidase conjugate (Accurate Scientific)diluted 1:10,000 in PBS-Tween. Peroxidase activity was determined usingTMB peroxidase substrate kit (Kirkegaard and Perry) with quantitation ofcolor intensity on a 96-well plate Molecular Devices spectrophotometerset to determine absorbance at 450 nM. Samples are evaluated using astandard curve of absorbance versus concentration. Four-parameterlogistics analysis generally is used to fit data and obtainconcentrations of unknown compounds.

TNF-α ELISA

Immulon 4 (Dynatech) 96-well plastic plates are coated with a 0.5 mg/mLsolution of mouse anti-human TNF-a monoclonal antibody. The secondaryantibody is a 1:2500 dilution of a rabbit anti-human TNF-α polyclonalserum purchased from Genzyme. All other operations are identical tothose described above for IL-1β. The standards are prepared inPBS-Tween+10% FBS or HS. Eleven two-fold dilutions are made beginning at20 ng/mL TNF-α.

IL-6 ELISA

Levels of secreted human IL-6 are also determined by specific trappingELISA as described previously in Chin and Kostura, J. Immunol.,151:5574–5585(1993). (Dynatech) ELISA plates are coated with mouseanti-human IL-6 monoclonal antibody diluted to 0.5 mg/mL in PBS. Thesecondary antibody, a rabbit anti-human IL-6 polyclonal antiserum, isdiluted 1:5000 with PBS-Tween. All other operations are identical tothose described above for IL-1β. The standards are prepared inPBS-Tween+10% FBS or HS. Eleven two-fold dilutions are made beginning at50 ng/mL IL-6.

PGE₂ Production

Prostaglandin E2 is detected in cell culture supernatants from LPS orIL-1 stimulated PBMC's using a commercially available enzymeimmunoassay. The assay purchased from the Cayman Chemical (Catalogue No.514010) and is run exactly according to the manufacturers instructions.

Interleukin-8 (IL-8)

The present compounds can also be assayed for IL-8 inhibitory activityas discussed below. Primary human umbilical cord endothelial cells(HUVEC) (Cell Systems, Kirkland, Wash.) are maintained in culture mediumsupplemented with 15% fetal bovine serum and 1% CS-HBGF consisting ofaFGF and heparin. The cells are then diluted 20-fold before being plated(250 μL) into gelatin coated 96-well plates. Prior to use, culturemedium is replaced with fresh medium (200 μL). Buffer or test compound(25 μL, at appropriate concentrations) is then added to each well inquadruplicate wells and the plates incubated for 6 h in a humidifiedincubator at 37° C. in an atmosphere of 5% CO₂. At the end of theincubation period, supernatant is removed and assayed for IL-8concentration using an IL-8 ELISA kit obtained from R&D Systems(Minneapolis, Minn.). All data is presented as mean value (ng/mL) ofmultiple samples based on the standard curve. IC₅₀ values whereappropriate are generated by non-linear regression analysis.

The compounds of this invention, in the above functional activity assay,suppress TNF-α in monocytes with IC₅₀ of less than 5 μM. Advantageously,the IC₅₀ should be less than 3 μM. Even more advantaeously, the IC₅₀should be less than 1 μM. Still more advantageously, the IC₅₀ should beless than 0.1 μM.

Further, in the other assays, the results from the present compounds arebetter than 5 μM. Advantageously, the IC₅₀ results should be less than 3μM. Even more advantaeously, the IC₅₀ should be less than 1 μM. Stillmore advantageously, the IC₅₀ should be less than 0.1 μM.

The ability of compounds of the present invention to inhibit theactivity of protozoa can be demonstrated using the following assays.

Anticoccidiosis Assay.

One-day-old White Leghorn chickens are obtained from a commercialhatchery and acclimated in a holding room. At three days of age the testanimals are selected by weight, wingbanded, and randomly placed onmedicated or control diets for the duration of the experiment. One ortwo replicates of two birds are utilized per treatment. Following 24 hpremedication, in each replicate one bird is infected with Eimeriaacervulina, the other bird is infected with E. tenella. Both strains ofEimeria are sensitive to all anticoccidial products, and have beenmaintained in laboratory conditions for over 25 years. The inoculaconsist of sporulated oocysts in tap water suspensions, administered ata dose rate of 0.25 mL per bird. The inocula levels are selected byprevious dose titrations to provide a low to moderate level ofinfection. The E. acervulina portion of the experiment is terminated onDay 5, the E. tenella on Day 6 post infection. The measured parametersare weight gain, feed consumption and oocyst production. E. tenellalesion scores are also recorded for background information. Treatmentswhich provide at least 80% reduction in oocyst production are consideredactive, those with 50–79% are considered partially active, and thosewith <50% are considered inactive. The same numerical categories inweight gain and feed consumption differentiate among treatments withgood, fair or poor productivity.

PKG Catalytic Assay

Kinase activity was detected using a peptide substrate and [³³P]-ATP. Analiquot containing enzyme (1 μl) was mixed with a reaction mix (10 μl)whose composition is as follows: 25 mM HEPES pH 7.4, 10 mM MgCl₂, 20 mMβ-glycerophosphate, 5 mM β mercaptoethanol, 10 μM cGMP, 1 mg/mL BSA, 400μM kemptide, 2 μM [³³P]ATP (0.1 mCi/ml). The reaction was allowed toproceed for 1 hour at room temperature prior to addition of phosphoricacid to a final concentration of 2.5 mM. Labeled peptide was captured onfilters using either P81 filters or on Millipore 96-well plates,MAPH-NOB (Millipore). In both cases filters were washed with 75 mMphosphoric acid, dried and [³³P]-ATP detected using scintillationcounting.

Enzyme Assay and Data Analysis

The peptide substrate biotinyl-ε-aminocaproyl-GRTGRRNSI-OH wassynthesized in house by standard methods. PET-cGMP, 1-NH₂-cGMP,8-APT-cGMP, and 8-NBD-cGMP were obtained from Biolog Life ScienceInstitute (Bremen, FRG), while 8-Br-cGMP came from Biomol ResearchLaboratories and 8-pCPT-cGMP came from Calbiochem. Bovine PKG wasobtained commercially; recombinant isoform Iα (Genbank Accession No.X16086) was purchased from Calbiochem, while native Iα enzyme waspurchased from Promega.

The kinase assay was performed in a 50 μL reaction volume containing 25mM HEPES (pH 7.0), 10 mM MgCl₂, 20 mM beta-glycerophosphate, 1 mM DTT,0.1 mg/mL bovine serum albumin, 20 μM ATP, 20 μM peptide substrate and2.5 μCi [gamma-³³P]ATP (Amersham). Cyclic nucleotide was seriallydiluted in buffer before adding 5 μL of each concentration into 40 μL ofthe assay mix. The reaction was initiated with 5 μL of enzyme (or bufferfor the background) and incubated for 30 minutes in a heating block at30° C. The assays were terminated by the addition of 25 μL 8Mguanidine-HCl solution (Pierce) before spotting 15 μL onto a SAM²streptavidin membrane (Promega). The membrane was washed twice with 1MNaCl and twice with 1M NaCl+1% H₃PO₄ on a rotating mixer for 20 minutes.The membrane was then rinsed successively with water and ethanol anddried under a heat lamp.

The individual assays were then separated, placed in scintillation vialscontaining 2 mL of Ultima Gold cocktail (Packard), and counted in aPackard TriCarb 2500 liquid scintillation counter. The amount of enzymewas adjusted to give between 10,000 and 140,000 cpm when maximallyactivated; substrate turnover was less than 10% in all cases. Theconcentration of Et-PKG varied between 0.26 and 3.4 μg/mL for cGMPtitrations and between 7 and 25 μg/mL for 8-NBD-cGMP titrations,depending on the activity of the enzyme form used. Assays with bovinePKG used 0.059 μg/mL recombinant or 0.034 μg/mL native enzyme with bothactivators. After subtracting the appropriate background for each assaypoint, titrations were fit to the following modified Hill equation usingKaleidagraph (Synergy Software):V _(A) =V ₀+(V _(max) −V ₀)/(1+(K _(A) /[A])^(h))

-   -   V_(A) is the observed velocity at concentration [A] of cyclic        nucleotide,    -   V₀ is the velocity in the absence of activator,    -   V_(max) is the velocity of the maximally activated enzyme,    -   K_(A) is the concentration for half maximal activation, and    -   h is the Hill coefficient. The activation parameters are        determined from a curve fit.        cGMP-Agarose Affinity Chromatography

Purification of PKG enzyme was perfoemed as follows. Chromatography oncGMP-agarose was performed according to the manufacturers instructions(Biolog, A019). Briefly, a 0.6 mL column was equilibrated with Buffer G(50 mM HEPES pH 7.4, 10% glycerol, 10 mM sodium fluoride, 0.1 mM sodiumorthovanadate, 1 mM EDTA). The sample (crude S100 extract or purifiedprotein) was mixed with an equal volume of Buffer G and applied to thecolumn; the column was then washed with 10 mL of the same buffer. Thecolumn was then washed with 10 mL of Buffer G containing 1 mM GMP. PKGwas then eluted with 10 mL of Buffer G containing 15 mM cGMP.

In the above assays, the compounds show selectivity, with inhibition ofthe parasitic enzyme with negligible inhibition of the host enzyme.Thus, it is advantageous that the parasite PKG enzyme IC50 be less than0.5 μM while the host PKG enzyme IC50 be greater than 1 μM. It is moreadvantageous that the host PKG IC50 be greater than 5 μM. It is alsomore advantageous that the parasite PKG enzyme IC50 be less than 0.1 μM.It is even more advantageous that the parasite PKG enzyme IC50 be lessthan 50 nM, and particularly advantageous that the parasite PKG enzymeIC50 be less than 10 nM.

Utility

The (pyrimidyl)(phenyl)substituted fused heteroaryl compounds of thepresent invention are useful as antiprotozoal agents. As such, they maybe used in the treatment and prevention of protozoal diseases in humanand animals, including poultry. Examples of protozoal diseases againstwhich compounds of formula I may be used, and their respective causativepathogens, include: 1) amoebiasis (Dientamoeba sp., Entamoebahistolytica); 2) giardiasis (Giardia lamblia); 3) malaria (Plasmodiumspecies including P. vivax, P. falciparum, P. malariae and P. ovale); 4)leishmaniasis (Leishmania species including L. donovani, L. tropica, L.mexicana, and L. braziliensis); 5) trypanosomiasis and Chagas disease(Trypanosoma species including T. brucei, T. theileri, T. rhodesiense,T. gambiense, T. evansi, T. equiperdum, T. equinum, T. congolense, T.vivax and T. cruzi); 6) toxoplasmosis (Toxoplasma gondii); 7) babesiosis(Babesia sp.); 8) cryptosporidiosis (Cryptosporidium sp.); 9) dysentery(Balantidium coli); 10) vaginitis (Trichomonas species including T.vaginitis, and Tritrichomonas foetus); 11) coccidiosis (Eimeria speciesincluding E. tenella, E. necatrix, E. acervulina, E. maxima and E.brunetti, E. mitis, E. bovis, E. melagramatis, and Isospora sp.); 12)enterohepatitis (Histomonas gallinarum), and 13) infections caused byAnaplasma sp., Besnoitia sp., Leucocytozoan sp., Microsporidia sp.,Sarcocystis sp., Theileria sp., and Pneumocystis carinii.

Dose Range:

Compounds of formula I may be administered to a host in need oftreatment in a manner similar to that used for other antiprotozoalagents; for example, they may be administered parenterally, orally,topically, or rectally. The dosage to be administered will varyaccording to the particular compound used, the infectious organisminvolved, the particular host, the severity of the disease, physicalcondition of the host, and the selected route of administration; theappropriate dosage can be readily determined by a person skilled in theart.

For the treatment of protozoal diseases in humans, the oral dosage mayrange from 1 mg/kg to 1000 mg/kg; and the parenteral dosage may rangefrom 0.5 mg/kg to 500 mg/kg. For veterinary therapeutic use, the oraldosage may range from 1 mg/kg to 1000 mg/kg; and the parenteral dosagemay range from 0.5 mg/kg to 500 mg/kg. For prophylactic use in humans,the oral dosage may range from 1 mg/kg to 1000 mg/kg; and the parenteraldosage may range from 0.5 mg/kg to 500 mg/kg.

Thus, the tablet, hard gelatin capsule, troche or lozenge convenientlywould have, for example, 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 25 mg, 100mg, 250 mg, 500 mg, or 1000 mg of the present compound. The tablet, hardgelatin capsule, troche or lozenge is given conveniently once, twice orthree times daily.

For prophylactic use in animal, the oral dosage may range from 1 mg/kgto 1000 mg/kg; and the parenteral dosage may range from 0.5 mg/kg to 500mg/kg. For use as an anticoccidial agent, particularly in poultry, thecompound may be administered in the animals' feed or drinking water inaccordance with common practice in the poultry industry and as describedbelow.

The compositions of the present invention comprises a compound offormula I and an inert carrier. The compositions may be in the form ofpharmaceutical compositions for human and veterinary usage, or in theform of feed composition for the control of coccidiosis in poultry.

The pharmaceutical compositions of the present invention comprise acompound of formula I as an active ingredient, and may also contain aphysiologically acceptable carrier and optionally other therapeuticingredients. The compositions include compositions suitable for oral,rectal, topical, and parenteral (including subcutaneous, intramuscular,and intravenous) administrations, although the most suitable route inany given case will depend on the particular host, and nature andseverity of the conditions for which the active ingredient is beingadministered. The pharmaceutical compositions may be convenientlypresented in unit dosage form and prepared by any of the methodswell-known in the art of pharmacy.

In practical use, compounds of formula I can be combined as the activeingredient in intimate admixture with a pharmaceutical carrier accordingto conventional pharmaceutical compounding techniques. The carrier maytake a wide variety of forms depending on the form of preparationdesired for administration, e.g., oral or parenteral (includingintravenous).

In preparing the compositions for oral dosage form, any of the usualpharmaceutical media may be employed. For example, in the case of oralliquid preparations such as suspensions, elixirs and solutions, water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like may be used; or in the case of oral solidpreparations such as powders, capsules and tablets, carriers such asstarches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents, and the like may beincluded. Because of their ease of administration, tablets and capsulesrepresent the most advantageous oral dosage unit form in which casesolid pharmaceutical carriers are obviously employed. If desired,tablets may be coated by standard aqueous or nonaqueous techniques. Inaddition to the common dosage forms set out above, compounds of formulaI may also be administered by controlled release means and/or deliverydevices.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient, as a powder or granules or as a solution or a suspension inan aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or awater-in-oil liquid emulsion. Such compositions may be prepared by anyof the methods of pharmacy but all methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more necessary ingredients. In general, thecompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet may be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing, in a suitable machine, theactive ingredient in a free-flowing form such as powder or granules,optionally mixed with a binder, lubricant, inert diluent, surface activeor dispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound moistened with an inertliquid diluent. Desirably, each tablet contains from about 1 mg to about500 mg of the active ingredient and each cachet or capsule contains fromabout 1 to about 500 mg of the active ingredient.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthese active compounds in water suitably mixed with a surfactant such ashydroxypropylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Suitable topical formulations include transdermal devices, aerosols,creams, ointments, lotions, dusting powders, and the like. Theseformulations may be prepared via conventional methods containing theactive ingredient. To illustrate, a cream or ointment is prepared bymixing sufficient quantities of hydrophilic material and water,containing from about 5–10% by weight of the compound, in sufficientquantities to produce a cream or ointment having the desiredconsistency.

Pharmaceutical compositions suitable for rectal administration whereinthe carrier is a solid may be presented as unit dose suppositories.Suitable carriers include cocoa butter and other materials commonly usedin the art, and the suppositories may be conveniently formed byadmixture of the combination with the softened or melted carrier(s)followed by chilling and shaping molds.

It should be understood that in addition to the aforementioned carrieringredients the pharmaceutical formulations described above may include,as appropriate, one or more additional carrier ingredients such asdiluents, buffers, flavoring agents, binders, surface-active agents,thickeners, lubricants, preservatives (including anti-oxidants) and thelike, and substances included for the purpose of rendering theformulation isotonic with the blood of the intended recipient.

For use in the management of coccidiosis in poultry, a compound offormula I may be conveniently administered as a component of a feedcomposition. Suitable poultry feed composition will typically containfrom about 1 ppm to about 1000 ppm, or from about 0.0005% to about 0.05%percent, by weight of a compound of formula I. The optimum levels willnaturally vary with the species of Eimeria involved, and can be readilydetermined by one skilled in the art.

In the preparation of poultry feed, a compound of formula I may bereadily dispersed by mechanically mixing the same in finely ground formwith the poultry feedstuff, or with an intermediate formulation (premix)that is subsequently blended with other components to prepare the finalpoultry feedstuff that is fed to the poultry. Typical components ofpoultry feedstuff include molasses, fermentation residues, corn meal,ground and rolled oats, wheat shorts and middlings, alfalfa, clover andmeat scraps, together with mineral supplements such as bone meal,calcium carbonate and vitamins.

When the compound according to the present invention is used as anadditive to the feed, it is typically incorporated into a “premix.” Thepremix contains the active agent or agents as well as physiologicallyacceptable carriers and feedstuffs. The premix is relativelyconcentrated and is adapted to be diluted with other carriers, vitaminand mineral supplements, and feedstuffs to form the final animal feed.Premixes which are intermediate in concentration of active agent betweena first premix and the final animal feed are sometimes employed in theindustry and can be used in implementing the present invention. Whenemploying the present compound as sole active agent, a premix desirablycontains the agent at a concentration of from 0.1 to 50.0% by weight.Preferred premixes will generally contain the present compound at aconcentration of from 0.5 to 25.0%, by weight. The identity of the othercomponents of the premix and ultimate animal feed is not critical. Infinal feeds, the concentration of the active agent is not critical andwill depend on various factors known to those skilled in the art. Suchfactors include the relative potency of the particular active agent andthe severity of the coccidial challenge. In general, a final feedemploying compound of the present invention as the sole anticoccidialwill contain from about 0.0005 to about 0.05% by weight of saidcompound, preferably from about 0.0005 to about 0.005%.

Compositions containing a compound of formula I may also be prepared inpowder or liquid concentrate form. In accordance with standardveterinary formulation practice, conventional water soluble excipients,such as lactose or sucrose, may be incorporated in the powders toimprove their physical properties. Thus one embodiment of suitablepowders of this invention comprises 50 to 100% w/w, and for example 60to 80% w/w of the compound and 0 to 50% w/w and for example 20 to 40%w/w of conventional veterinary excipients. These powders may either beadded to animal feedstuff, for example by way of an intermediate premix,or diluted in animal drinking water.

Liquid concentrates of this invention suitably contain a water-solublecompound combination and may optionally include a veterinarilyacceptable water miscible solvent, for example polyethylene glycol,propylene glycol, glycerol, glycerol formal or such a solvent mixed withup to 30% v/v of ethanol. The liquid concentrates may be administered tothe drinking water of animals, particularly poultry.

The present invention contemplates using a compound of formula (I) assole anticoccidial agent as well as in combination with one or moreother anticoccidial agents. Suitable anticoccidials for combination useinclude, but are not limited to, amprolium, ethopabate, clopidol,meticlorpindol, decoquinate, dinitolmide, halofuginone, lasalocid,maduramicin, monensin, narasin, nicarbazin, chlortetracycline,oxytetracycline, robenidine, salinomycin, semduramicin, and diclazuril.When used in combination with one or more other anticoccidial agent, thecompound of formula (I) may be administered at or lower than theeffective doses when used alone; for example, the final feed may containabout 0.0001 to about 0.02% by weight, or preferably from about 0.0005to about 0.005% of a compound of formula (I). Similarly, the secondanticoccidial agent in the combination may be used in an amount at orlower than those commonly used as a sole anticoccidial. The combinationmay be formulated into medicament for poultry use as describedpreviously.

The formulated medicament may contain, in addition to anticoccidialagent(s) other therapeutic or nutritional agents commonly administeredto poultry in the feed or drinking water; such other agents may be, forexample, parasiticides, antibacterials, and growth promoters.

The compounds of the invention are prepared by the following reactionscheme(s). All substituents are as defined above unless indicatedotherwise.

Pyrimidyl imidazopyrimidines of formula (IA1) and (IA2) may be preparedaccording to the procedure shown in Scheme 6 below.

Pyrimidyl indazoles of formula (IB) may be prepared according to theprocedure shown in Scheme 7 below.

Pyrimidyl benzimidazoles of formula (ID) may be prepared according tothe procedure shown in Scheme 8 below.

The following examples illustrate the preparation of some of thecompounds of the invention and are not to be construed as limiting theinvention disclosed herein.

INTERMEDIATE COMPOUND 2

2-Aminopicoline (100 g, 924.7 mmol) was suspended in methylene chloride(1000 mL), cooled to 0° C. and treated dropwise with acetic anhydride(94 mL, 1000 mmol) over a period of 20 min., followed by addition oftriethyl amine (101 g, 1000 mmol). The resulting homogeneous solutionwas warmed up to room temperature and then concentrated to dryness underreduced pressure. The resulting residue was taken up in ethyl acetate(500 mL) and water (100 mL), and the pH was then adjusted to 6.0 with 2NHCl or NaOH. The organic layer was separated, dried over anhydroussodium sulfate, filtered, and evaporated. Recrystallization of theresidue from ethyl acetate/hexane gave INTERMEDIATE COMPOUND 2 (101 g).

INTERMEDIATE COMPOUND 3

The amide INTERMEDIATE COMPOUND 2 (62.9 g, 419 mmol) was dissolved inwater (650 mL) by warming to 60°. Potassium permanganate (30.6 g) wasadded and the stirred mixture was heated to 75° C. Additional KMnO₄(30.6 g) was added, and the mixture was heated to reflux. After 3 h. ofreflux, the mixture was cooled to 75° C. and additional KMnO₄ (70.2 g)was added cautiously in small portions and refluxed for 15 h. Themixture was cooled to room temperature, filtered over celite andextracted with diethyl ether. The aqueous layer was neutralized with 2NHCl to pH 7.0 and evaporated to yield 86 g of INTERMEDIATE COMPOUND 3which was used in the preparation of INTERMEDIATE COMPOUND 4 belowwithout further purification.

INTERMEDIATE COMPOUND 4

The acid INTERMEDIATE COMPOUND 3 (10.0 g, 55.6 mmol) was suspended inabsolute ethanol (300 mL) at room temperature, HCl gas was bubbled for10 minutes and then refluxed for 6 h. The ethanol was removed underreduced pressure, the resulting viscous liquid was neutralized with std.sodium bicarbonate and the mixture was extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulfate, filtered andevaporated to yield the ester INTERMEDIATE COMPOUND 4 (2.42 g).

INTERMEDIATE COMPOUND 5

To a solution of the ester INTERMEDIATE COMPOUND 4 (48.2 g, 290 mmol) inanhydrous tetrahydrofuran (480 mL) at −30° C., lithium aluminum hydride(1.0M in THF, 580 mL, 580 mmol) was added dropwise. The resultingsolution was warmed to 0° C. and then refluxed for 1 h. The resultingsolution was cooled to room temperature, quenched with water (15.4 mL)followed by addition of NaOH (5N, 15.4 mL) and filtration. The filtratewas evaporated and triturated with diethyl ether to yield the alcoholINTERMEDIATE COMPOUND 5 (25.4 g).

Alternatively, the alcohol INTERMEDIATE COMPOUND 5 could be made from2-chloro isonicotinic acid by the following sequence of reactions: i)reduction with diborane to alcohol, ii) conversion to tetrazolopyridinewith ammonium azide and iii) reduction of the tetrazolopyridine to2-amino pyridine with zinc in acetic acid or tin dichloride.

INTERMEDIATE COMPOUND 6

To 2-mercapto-4-methylpyrimidine.HCl (20 g, 123 mmol) in toluene (300mL) at room temperature under argon, diisopropylethylamine (34.6 mL,184.5 mmol) and N,N-dimethylformamide dimethyl acetal (40 mL, 301 mmol)were added, refluxed for 4 h., cooled to room temperature and thenconcentrated under reduced pressure. The resulting viscous liquid wasdissolved in diethyl ether (200 mL), diluted with water (50 mL) and thepH adjusted to 5.0 with sodium bisulfate (aq. sat.). The organic phasewas dried over anhydrous sodium sulfate and concentrated to yieldINTERMEDIATE COMPOUND 6 (15.3 g) as a light brown oil.

INTERMEDIATE COMPOUND 7

To a solution of INTERMEDIATE COMPOUND 6 (6.3 g, 45.0 mmol) in THF (100mL, anhydrous) at −78° C. under argon, lithium diisopropyl amide (2.0Min THF, 27.0 mL, 54.0 mmol) was added dropwise. The resulting solutionwas stirred for 1 hr at −78° C. and then treated dropwise with asolution of methyl 4-fluorobenzoate (6.4 g, 49.5 mmol) in THF (20 mL,anhydrous). The mixture was stirred for 2 h. at −78°, and then warmed upto room temperature. The resulting solution was quenched with ammoniumchloride (aq. sat.) and extracted with ethyl acetate. The organic phasewas concentrated and purified by flash column chromatography (silica,15:85=EtOAc:Hexane) to yield the ketone INTERMEDIATE COMPOUND 7 (7.58g).

INTERMEDIATE COMPOUND 8

Tetrabutylammonium tribromide (52.3 g, 108 mmol) was added to the ketoneINTERMEDIATE COMPOUND 7 (28.5 g, 108 mmol) suspended in carbontetrachloride (325 mL) at room temperature. After 15 minutes, methylenechloride (650 mL) was added. The resulting solution was stirred for 4hours at room temperature. The reaction mixture was quenched with sodiumbicarbonate (250 mL, sat., aq.) and extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated to a brown oil INTERMEDIATE COMPOUND 8 (78 g) which wasused in the next step to prepare COMPOUND 9 without furtherpurification.

INTERMEDIATE COMPOUND 9

To a solution of the crude bromide INTERMEDIATE COMPOUND 8 (5.45 g, 16.0mmol) in absolute ethanol (30 mL) at room temperature, the alcoholINTERMEDIATE COMPOUND 5 (894 mg, 7.2 mmol) dissolved in absolute ethanol(20 mL, anhydrous) was added dropwise. The combined solution was heatedto 60° C. overnight under argon. The resulting solution was diluted withsodium bicarbonate (sat., aq.) and extracted with ethyl acetate. Theorganic phase was dried over anhydrous sodium sulfate, filtered,concentrated, and purified by flash silica column chromatography (60:40EtOAc:Hexane first, then 100% EtOAc) to yield the imidazopyridineINTERMEDIATE COMPOUND 9 (806 mg).

INTERMEDIATE COMPOUND 10

The imidazopyridine INTERMEDIATE COMPOUND 9 (322 mg, 0.88 mmol) inmethanol (25 mL) at room temperature was treated dropwise with asolution of oxone (1082 mg, 1.76 mmol) in water (10 mL). The resultingmixture was stirred at room temperature overnight and extracted withethyl acetate. The organic phase was dried over anhydrous sodiumsulfate, filtered, concentrated, and purified by flash columnchromatography (silica, 55:45 EtOAc:Hexane) to yield the sulfoneINTERMEDIATE COMPOUND 10 (301 mg).

COMPOUND 14 (EXAMPLE A04)

Method I:Step A:

COMPOUND 11 (EXAMPLE A01)

A suspension of the sulfone INTERMEDIATE COMPOUND 10 (300 mg, 0.75 mmol)in (S)-(−)-alpha-methylbenzylamine (6.0 mL) was heated to 60° C. for 4 hwhile stirring under an atmosphere of argon. The resulting solution wascooled to room temperature, acidified with citric acid (5%, aq.) topH=4.5 and extracted with ethyl acetate. The organic phase was driedover anhydrous sodium sulfate, filtered, concentrated, and purified byflash column chromatography (5:95 10% NH₄OH in MeOH: CH₂Cl₂) to yieldthe amine EXAMPLE A01 (307 mg).

Step B:

COMPOUND 12 (EXAMPLE A02)

To a solution of EXAMPLE A01 (75 mg, 0.17 mmol) in toluene (3.0 mL) at0° C. under argon, 1,8-diazabicyclo[5.4.0]undec-7-ene (0.062 mL, 0.40mmol) and diphenylphosphoryl azide (0.088 mL, 0.40 mmol) were added. Theresulting solution was stirred at room temperature overnight,concentrated, and purified by prep silica gel TLC (50:50 EtOAc:Hexane)to give the azide EXAMPLE A02 (47 mg).

Step C:

COMPOUND 13 (EXAMPLE A03)

To a solution of the azide EXAMPLE A02 (45 mg, 0.10 mmol) in THF (1.5mL) at room temperature, triphenylphosphine (65 mg, 0.25 mmol) and water(1.5 mL) were added and stirred at room temperature overnight. Theresulting solution was diluted with water, extracted with ethyl acetate,and the organic phase was concentrated and purified by prep silica gelTLC (5:95=10% NH₄OH in MeOH:CH₂Cl₂) to yield the amine EXAMPLE A03 (29mg).

Step D:

EXAMPLE A04

To the solution of the amine EXAMPLE A03 (29 mg, 0.10 mmol) in methanol(1.0 mL) at room temperature under argon, acetic acid (glacial, 0.033mL), formaldehyde (36˜38% in water, 0.033 mL) and sodiumcyanoborohydride (1.0M in THF, 0.52 mL, 0.52 mmol) were added andstirred at room temperature overnight. The resulting solution wasconcentrated and purified by prep silica gel TLC (10:90 10% NH₄OH inMeOH:CH₂Cl₂) to yield the dimethyl amine EXAMPLE A04 (26 mg).

INTERMEDIATE COMPOUND 18

Method II:

INTERMEDIATE COMPOUND 15

Step A:

Treatment of INTERMEDIATE COMPOUND 10 with neopentyl amine following theprocedure described in Method I, Step A gave INTERMEDIATE COMPOUND 15.

Step B:

To a stirred solution of INTERMEDIATE COMPOUND 15 (937 mg, 2.31 mmol) inchloroform (15 mL) at −10° C., was added triethyl amine (0.64 mL, 4.62mmol) followed by methane sulfonyl chloride (0.197 mL). After 4 h., theresulting mesylate COMPOUND 16 (EXAMPLE A06) was treated withdimethylamine (2M in THF, 5 mL) and stirring continued overnight at roomtemperature. The following day, the solution was evaporated and purifiedby flash column chromatography (silica, 0.6% NH4OH, 5.4% methanol, 94%methylene chloride) to yield INTERMEDIATE COMPOUND 18 (720 mg).

COMPOUND 20 (EXAMPLE A20)

In a pressure vessel, the sulfone INTERMEDIATE COMPOUND 10 (1.1 g) wassuspended in tetrahydrofuran (65 mL) saturated with ammonia at −20° C.The tube was closed, warmed up to room temperature and stirred for twodays. The vessel was cooled to −35° C., opened, warmed up to roomtemperature, and then evaporated under reduced pressure. The resultingresidue was purified by flash column chromatography (silica, 9% methanolwith 1% ammonium hydroxide, 90% methylene chloride) to yield the amineCOMPOUND 19 (EXAMPLE A09) (895 mg). Treatment of EXAMPLE A09 (729 mg,2.17 mmol) in methylene chloride (10 mL) sequentially with triethylamine(0.453, 3.26 mmol), methane sulfonyl chloride (0.185 mL, 2.39 mmol)followed by the treatment of the mesylate with a solution of 2Mdimethylamine in tetrahydrofuran as shown in Method II, Step B gaveEXAMPLE A20 (215 mg).

Method III

COMPOUND 17 (EXAMPLE A07)

Step A:

To a solution of EXAMPLE A01 (150 mg, 0.34 mmol) in methylene chloride(15 mL), manganese dioxide (300 mg) was added and stirred for 6 h.Filtration over celite and purification by prep TLC (silica, 0.5% NH4OH,4.5% methanol, 95% methylene chloride) gave the aldehyde COMPOUND 17(EXAMPLE A07) (122 mg).

Step B:

COMPOUND 14 (EXAMPLE A04)

To the aldehyde EXAMPLE A07 (30 mg, 0.074 mmol) in methylene chloride (1mL) was added dimethyl amine (2M in THF, 0.056 mL, 0.117 mmol),diisopropylethylamine (0.042 mL, 0.222 mmol), sodiumtiracetoxyborohydride (31.1 mg, 0.148 mmol) and stirred for 4 h. Theresulting solution was concentrated and purified by prep silica gel TLC(10:90 10% NH₄OH in MeOH:CH₂Cl₂) to yield the dimethyl amine EXAMPLE A04(21 mg).

COMPOUND II (EXAMPLE 1)

EXAMPLE 1 was prepared under conditions similar to those used for thesynthesis of INTERMEDIATE COMPOUND 15. The key cyclization reaction toform the imidazopyridine ring required the use of2-amino-3-benzyloxypyridine (2.5 equivalents) in isopropanol solvent ata concentration of 0.2 M, heated at 90° C. for 14 h. The resultingmixture was then concentrated in vacuo and purified by flashchromatography (Biotage 40S, SiO₂, 20% EtOAc-hexane) to provide theimidazopyridine cyclization product. This intermediate was elaboratedinto EXAMPLE 1 using methodology displayed in Schemes 2–4 and wascharacterized by ¹H NMR, HPLC and mass spectrometry (m/z: 482 (M⁺+1)).

EXAMPLES 2–32

The following imidazopyridines were prepared under conditions similar tothose displayed in Schemes 1–5. The 2,4-difluorophenyl moiety ofEXAMPLES 2–6 was introduced by the substitution of methyl2,4-difluorobenzoate in place of methyl 4-fluorobenzoate shown in Scheme2. The 3-trifluoromethylphenyl moiety of EXAMPLES 7–11 was introduced bythe substitution of methyl 3-trifluoromethylbenzoate in place of methyl4-fluorobenzoate also shown in Scheme 2. The 2-chloro-4-fluorophenylmoiety of EXAMPLES 12–14 was introduced by the substitution of methyl2-chloro-4-fluorobenzoate in place of methyl 4-fluorobenzoate also shownin Scheme 2. The 2-chlorophenyl moiety of EXAMPLES 15 and 16 wasintroduced by the substitution of methyl 2-chlorobenzoate in place ofmethyl 4-fluorobenzoate also shown in Scheme 2. The 4-chlorophenylmoiety of EXAMPLES 17 and 18 was introduced by the substitution ofmethyl 4-chlorobenzoate in place of methyl 4-fluorobenzoate also shownin Scheme 2. The 3,4-dichlorophenyl moiety of EXAMPLES 19 and 20 wasintroduced by the substitution of methyl 3,4-dichlorobenzoate in placeof methyl 4-fluorobenzoate also shown in Scheme 2. The2,3-dichlorophenyl moiety of EXAMPLES 21 and 22 was introduced by thesubstitution of methyl 2,3-dichlorobenzoate in place of methyl4-fluorobenzoate also shown in Scheme 2. The cyclohexylamine moiety inEXAMPLES 4 and 5 was introduced by the substitution of cyclohexylaminein place of neopentylamine shown in Scheme 4. The alcohol moiety inEXAMPLE 27 was introduced by the substitution of (R)-phenyl glycinol inplace of neopentylamine shown in Scheme 4. The hydroxyneopentylaminemoiety in EXAMPLES 24–26 was introduced by the substitution of2,2-dimethyl-3-amino-1-propanol in place of neopentylamine displayed inScheme 4. The sulfonamide moiety in EXAMPLE 26 was introduced bytreatment with methanesulfonyl chloride prior to the introduction of the2,2-dimethyl-3-amino-1-propanol subunit. The methyl ether moiety inEXAMPLE 6 was introduced by the substitution of sodium methoxide inplace of dimethylamine displayed in Scheme 4. The methyl sulfone moietyin EXAMPLE 31 was introduced by the substitution of sodium thiolate inplace of dimethylamine shown in Scheme 4 to provide the methyl sulfideintermediate. This methyl sulfide was then oxidized with 2 equivalentsof oxone in 2:1 methanol-water to provide the methyl sulfone in EXAMPLE31. The dimethyl phosphonate moiety in EXAMPLE 30 was introduced by thesubstitution of sodium dimethylphosphite in place of dimethylaminedescribed in Scheme 4. The morpholine moiety in EXAMPLE 7 was introducedby the substitution of morpholine in place of dimethylamine described inScheme 4. The dimethylaminoethylpiperazine moiety in EXAMPLE 8 wasintroduced by the substitution ofN-(2-(N,N-dimethylamino)ethyl)piperazine in place of dimethylaminedescribed in Scheme 4. The isopropylpiperazine moiety in EXAMPLE 9 wasintroduced by the substitution of N-isopropylpiperazine in place ofdimethylamine shown in Scheme 4. The methylamine moiety in EXAMPLE 25was introduced by the substitution of methylamine (2M in THF) in placeof dimethylamine shown in Scheme 4. The sulfonamide moiety in Example 28was introduced by treating the analogous neopentyl derivative of EXAMPLEA03 (COMPOUND 13) shown in Scheme 3 with methanesulfonyl chloride. Thissulfonamide was subsequently alkylated with KHMDS/MeI to provide EXAMPLE29. EXAMPLES 23–24 (Z═H) and 27 (Z═CH₃) were prepared under conditionswhere 2-amino-4-hydroxymethylpyridine (INTERMEDIATE COMPOUND 5) wassubstituted by 2-aminopyridine and 2-amino-4-picoline respectively asshown in Scheme 2. The aldehydes in EXAMPLES 13 and 32 were prepared byoxidation of EXAMPLE 12 and INTERMEDIATE COMPOUND 15 (Scheme 4) usingDess-Martin periodinane in methylene chloride in a similar manner shownin Scheme 5. With the exception of EXAMPLE 16 (¹H NMR only), thefollowing imidazopyridines were characterized by ¹H NMR, HPLC and massspectrometry.

The following TABLE 1 of EXAMPLES 2–32 refer to the following generalchemical structure:

TABLE 1

EX. Ar Group R Group Z Group MS (m/z) 2 2,4-Difluorophenyl NHCH₂C(CH₃)₃CH₂OH 424 (M⁺+1) 3 2,4-Difluorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 451 (M⁺+1)4 2,4-Difluorophenyl

CH₂OH 436 (M⁺+1) 5 2,4-Difluorophenyl

CH₂N(CH₃)₂ 463 (M⁺+1) 6 2,4-Difluorophenyl NHCH₂C(CH₃)₃ CH₂OCH₃ 438(M⁺+1) 7 3-Trifluoromethylphenyl NHCH₂C(CH₃)₃

525 (M⁺+1) 8 3-Trifluoromethylphenyl NHCH₂C(CH₃)₃

595 (M⁺+1) 9 3-Trifluoromethylphenyl NHCH₂C(CH₃)₃

566 (M⁺+1) 10 3-Trifluoromethylphenyl NHCH₂C(CH₃)₃ CH₂OH 458 (M⁺+1) 113-Trifluoromethylphenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 483 (M⁺+1) 122-Chloro-4-fluorophenyl NHCH₂C(CH₃)₃ CH₂OH 442 (M⁺+1) 132-Chloro-4-fluorophenyl NHCH₂C(CH₃)₃ CHO 438 (M⁺+1) 142-Chloro-4-fluorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 467 (M⁺+1) 152-Chlorophenyl NHCH₂C(CH₃)₃ CH₂OH 422 (M⁺+1) 16 2-ChlorophenylNHCH₂C(CH₃)₃ CH₂N(CH₃)₂ — 17 4-Chlorophenyl NHCH₂C(CH₃)₃ CH₂OH 422(M⁺+1) 18 4-Chlorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 450 (M⁺+1) 193,4-Dichlorophenyl NHCH₂C(CH₃)₃ CH₂OH 457 (M⁺+1) 20 3,4-DichlorophenylNHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 484 (M⁺+1) 21 2,3-Dichlorophenyl NHCH₂C(CH₃)₃CH₂OH 457 (M⁺+1) 22 2,3-Dichlorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 484(M⁺+1) 23 4-Fluorophenyl NHCH₂C(CH₃)₃ H 376 (M⁺+1) 24 4-FluorophenylNHCH₂C(CH₃)₂CH₂OH H 392 (M⁺+1) 25 4-Fluorophenyl NHCH₂C(CH₃)₂CH₂OHCH₂NHCH₃ 435 (M⁺+1) 26 4-Fluorophenyl NHCH₂C(CH₃)₂CH₂OH CH₂N(CH₃)SO₂CH₃513 (M⁺+1) 27 4-Fluorophenyl

CH₃ 440 (M⁺+1) 28 4-Fluorophenyl NHCH₂C(CH₃)₃ CH₂NHSO₂CH₃ 483 (M⁺+1) 294-Fluorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)SO₂CH₃ 497 (M⁺+1) 30 4-FluorophenylNHCH₂C(CH₃)₃ CH₂PO(OMe)₂ 498 (M⁺+1) 31 4-Fluorophenyl NHCH₂C(CH₃)₃CH₂SO₂CH₃ 468 (M⁺+1) 32 4-Fluorophenyl NHCH₂C(CH₃)₃ CHO 404 (M⁺+1)

EXAMPLE 33A (COMPOUND III) AND EXAMPLE 33B (COMPOUND IV)

Compounds (III) and (IV) were prepared from INTERMEDIATE COMPOUND 7 asshown in Schemes 2 and 6. Thus, the methylsulfide INTERMEDIATE COMPOUND7 (8 g, 30.7 mmol) was diluted into 2:1 MeOH—H₂O (700 mL), oxone (38 g,61.4 mmol) added, and the suspension stirred at 23° C. for 15 h. Theresulting reaction mixture was concentrated in vacuo, and the residuepurified by flash column chromatography (Biotage 40M, SiO₂, 50%EtOAc-hexane) to provide the sulfone intermediate (6.8 g). This material(6.8 g, 23.2 mmol) was diluted into dichloroethane (100 mL) andneopentylamine (6.1 g, 69.5 mmol) added.

The resulting reaction mixture was heated at 50° C. for 15 h., cooled,partitioned between aqueous sodium bicarbonate and methylene chloride,the organic phase dried with anhydrous sodium sulfate, and concentratedin vacuo. The residue was purified by flash column chromatography(Biotage 40M, SiO₂, 15% EtOAc-hexane) to provide the aminopyrimidineintermediate (2 g). This material (1.9 g, 6.45 mmol) was diluted into2:1 methylene chloride-CCl₄ (60 mL) and treated with tetrabutylammoniumtribromide (3.4 g, 7.1 mmol) added. The reaction mixture was maintainedat 23° C. for 30 min., partitioned between aqueous sodium bicarbonateand methylene chloride, the organic phase dried with anhydrous sodiumsulfate, and concentrated in vacuo.

The resulting residue was purified by flash column chromatography(Biotage 40M, SiO₂, 5–20% EtOAc-hexane) to provide the bromideintermediate (2.2 g). This material (200 mg, 0.53 mmol) was diluted intoNMP (0.53 mL) and treated with 2-aminopyrimidine (505 mg, 5.3 mmol). Theresulting reaction mixture was maintained at 135° C. for 4 h., cooled,and purified by flash column chromatography (Biotage 40M, SiO₂, 20%EtOAc-hexane) to provide a mixture of two regioisomeric products. Thismixture was separated by preparative thin layer chromatography (3×1500u, SiO₂, 2% methanol-chloroform) to provide (III) and (IV) which wereeach characterized by ¹H NMR, HPLC and mass spectrometry (m/z: 377(M⁺+1)) for (III) and (m/z: 377 (M⁺+1)) for (IV).

EXAMPLE 34 (COMPOUND V)

Compound (V) was prepared under conditions similar to those used for thesynthesis of INTERMEDIATE COMPOUND 15. The key cyclization reaction toform the imidazoisoquinoline ring required the use ofisoquinolin-3-amine (2.5 equivalents) in isopropanol solvent at aconcentration of 0.2M, heated at 90° C. for 14 h. The mixture was thenconcentrated in vacuo and purified by flash chromatography (Biotage 40S,SiO₂, 20% EtOAc-hexane) to provide the imidazoisoquinoline cyclizationproduct. This intermediate was elaborated into (V) using methodologydisplayed in Schemes 2–4 and was characterized by ¹H NMR, HPLC and massspectrometry (m/z: 426 (M⁺+1)).

EXAMPLE 35 (COMPOUND VI)

EXAMPLE 35 was prepared under conditions similar to those used for thesynthesis of INTERMEDIATE COMPOUND 15. The key cyclization reaction toform the imidazoisoquinoline ring required the use of1-aminoisoquinoline (2.5 equivalents) in isopropanol solvent at aconcentration of 0.2M, heated at 90° C. for 14 h. The resulting mixturewas then concentrated in vacuo and purified by flash chromatography(Biotage 40S, SiO₂, 20% EtOAc-hexane) to provide the imidazoisoquinolinecyclization product. This intermediate was elaborated into (VI) usingmethodology displayed in Schemes 2–4 and was characterized by ¹H NMR,HPLC and mass spectrometry (m/z: 426 (M⁺+1)).

EXAMPLE 36 (COMPOUND VII)

Compound (VII) was prepared under conditions similar to those used forthe synthesis of INTERMEDIATE COMPOUND 15. The key cyclization reactionto form the imidazotriazine ring required the use of3-amino-1,2,4-triazine (2.5 equivalents) in isopropanol solvent at aconcentration of 0.2M, heated at 90° C. for 14 h. The resulting mixturewas then concentrated in vacuo and purified by flash chromatography(Biotage 40M, SiO₂, 70% EtOAc-hexane) to provide the imidazotriazinecyclization product in 38% yield. This intermediate was elaborated into(VII) using methodology displayed in Schemes 2–4 and was characterizedby ¹H NMR, HPLC and mass spectrometry (m/z: 378 (M⁺+1)).

EXAMPLE 37 (COMPOUND VIII)

Compound (VIII) was prepared under conditions similar to those used forthe synthesis of INTERMEDIATE COMPOUND 15. The key cyclization reactionto form the imidazobenzimidazole ring required the use of2-amino-1-methylbenzimidazole (2.5 equivalents) in isopropanol solventat a concentration of 0.2M, heated at 90° C. for 14 h. The resultingmixture was then concentrated in vacuo and purified by flashchromatography (Biotage 40M, SiO₂, 70% EtOAc-hexane) to provide theintermediate hydrated pre-cyclization product. This intermediate wasdehydrated with Burgess Reagent (5 equivalents) in dioxane at 90° C. for12 h to form the imidazobenzimidazole cyclization product (30% yield)which was elaborated into (VIII) using methodology displayed in Schemes2–4 and was characterized by ¹H NMR, HPLC and mass spectrometry (m/z:429 (M⁺+1)).

EXAMPLE 38 (COMPOUND IX)

Compound (IX) was prepared under conditions similar to those used forthe synthesis of INTERMEDIATE COMPOUND 15. The key cyclization reactionto form the imidazothiazole ring required the use of 2-aminothiazole (3equivalents) in isopropanol solvent at a concentration of 0.2M, heatedat 90° C. for 14 h. The mixture was then concentrated in vacuo andpurified by flash chromatography (Biotage 40M, SiO₂, 25% EtOAc-hexane)to provide the imidazotriazine cyclization product in 41% yield. Thisintermediate was elaborated into (IX) using methodology displayed inSchemes 2–4 and was characterized by ¹H NMR, HPLC and mass spectrometry(m/z: 382 (M⁺+1)).

EXAMPLES 39–64

The following imidazothiazoles were prepared under conditions similar tothose described in EXAMPLE 38 for the synthesis of (IX). The2,4-difluorophenyl moiety of EXAMPLE 39 was introduced by thesubstitution of methyl 2,4-difluorobenzoate in place of methyl4-fluorobenzoate shown in Scheme 2. The 3-trifluoromethylphenyl moietyof EXAMPLES 40–42 was introduced by the substitution of methyl3-trifluoromethylbenzoate in place of methyl 4-fluorobenzoate shown inScheme 2. The R-Groups in EXAMPLES 41–64 were introduced by thesubstitution of the respective amines in place of neopentylamine shownin Scheme 4. The following imidazothiazoles were characterized by ¹HNMR, HPLC and mass spectrometry.

The following TABLE 2 of EXAMPLES 39–64 refer to the following generalchemical structure:

TABLE 2

EX. Ar Group R Group MS (m/z) 39 2,4-Difluorophenyl NHCH₂C(CH₃)₃ 400(M⁺+1) 40 3- NHCH₂C(CH₃)₃ 432 (M⁺+1) Trifluoromethylphenyl 413-Trifluoromethylphenyl

466 (M⁺+1) 42 3- NH(CH₂)₃OCH₃ 434 (M⁺+1) Trifluoromethylphenyl 434-Fluorophenyl

436 (M⁺+1) 44 4-Fluorophenyl

470 (M⁺+1) 45 4-Fluorophenyl

446 (M⁺+1) 46 4-Fluorophenyl NHCH₂C(CH₃)₂CH₂OH 398 (M⁺+1) 474-Fluorophenyl

466 (M⁺+1) 48 4-Fluorophenyl

466 (M⁺+1) 49 4-Fluorophenyl

416 (M⁺+1) 50 4-Fluorophenyl NH(CH₂)₃OCH₃ 384 (M⁺+1) 51 4-Fluorophenyl

380 (M⁺+1) 52 4-Fluorophenyl

394 (M⁺+1) 53 4-Fluorophenyl

416 (M⁺+1) 54 4-Fluorophenyl

432 (M⁺+1) 55 4-Fluorophenyl

502 (M⁺+1) 56 4-Fluorophenyl

446 (M⁺+1) 57 4-Fluorophenyl

460 (M⁺+1) 58 4-Fluorophenyl

460 (M⁺+1) 59 4-Fluorophenyl

476 (M⁺+1) 60 4-Fluorophenyl

448 (M⁺+1) 61 4-Fluorophenyl

446 (M⁺+1) 62 4-Fluorophenyl

412 (M⁺+1) 63 4-Fluorophenyl

410 (M⁺+1) 64 4-Fluorophenyl

396 (M⁺+1)

INTERMEDIATE COMPOUND X

To a solution of Me(MeO)NH—HCl (4.9 g, 50.7 mmol), EDCI (2.1 g, 11.2mmol) and DIEA (10.6 mL, 60.9 mmol) in 1:1 DMF-CH₂Cl₂ (75 mL) at 0° C.was added 3-nitro-4-(hydroxymethyl)benzoic acid (2 g, 10.1 mmol) in 1:1DMF-CH₂Cl₂ (50 mL). The resulting reaction mixture was warmed to 23° C.,maintained 15 h., partitioned between NH₄Cl_((aq)) and CH₂Cl₂, theorganic phase washed with NaHCO_(3(aq)), then dried over anhydroussodium sulfate and concentrated in vacuo. The crude product (1.4 g, 5.8mmol) was then diluted into acetonitrile (40 mL) and treated with MnO₂(2.5 g, 29.2 mmol). The resulting reaction mixture was maintained at 23°C. for 15 h., filtered through celite and concentrated in vacuo. Thecrude material was purified by flash column chromatography (SiO₂,acetone-hexane) to provide 880 mg of product which was characterized by¹H NMR, HPLC and mass spectrometry (m/z: 239 (M⁺+1)).

This material (800 mg, 3.3 mmol) was then diluted into toluene (3.3 mL),4-fluoroaniline (0.35 mL, 3.6 mmol) was added, and the resultingreaction mixture was heated at 100° C. Concentration in vacuo of thereaction mixture provided 900 mg (2.7 mmol) of crude product which wasdiluted into triethyl phosphite (3 mL) and heated at 150° C. for 15 h.,the excess triethyl phosphite removed by distillation, and the residuepurified by flash column chromatography (SiO₂, acetone-hexane) toprovide 680 mg of (X) which was characterized by ¹H NMR, HPLC and massspectrometry (m/z: 300 (M⁺+1)).

INTERMEDIATE COMPOUND XI

INTERMEDIATE COMPOUND X (660 mg, 2.2 mmol) was diluted into glacialacetic acid (15 mL) and slowly treated with a solution of bromine (0.11mL, 350 mg, 2.2 mmol) in glacial acetic acid (10 mL) over 3 h. Theresulting reaction mixture was maintained at 23° C. for 15 h., pouredinto ice water, filtered, and the residue purified by flash columnchromatography (SiO₂, acetone-hexane) to provide 550 mg of product whichwas characterized by ¹H NMR, HPLC and mass spectrometry (m/z: 378(M⁺+1)).

This material (25 mg, 0.068 mmol) was then diluted into DMF (0.5 mL),2-chloro-4-(trimethylstannyl)pyrimidine (38 mg, 0.14 mmol) was added,followed by Pd₂(dba)₃ (4 mg) and P(o-tol)₃ (2.5 mg), and the reactionmixture was heated at 100° C. The reaction mixture was concentrated invacuo and the residue purified by preparative thin layer chromatography(SiO₂, 5% MeOH—CH₂Cl₂) to provide 20 mg of (XI) which was characterizedby ¹H NMR, HPLC and mass spectrometry (m/z: 412 (M⁺+1)).

EXAMPLE 67 (COMPOUND XII)

COMPOUND XI (20 mg, 0.049 mmol) was diluted into DMSO (0.5 mL) andtreated with neopentylamine (0.011 mL, 0.097 mmol). The resultingreaction mixture was maintained at 100° C. for 15 h., and the reactionmixture partitioned between water and chloroform, the organic phasedried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography (SiO₂, 5%MeOH—CH₂Cl₂) to provide 10 mg of COMPOUND XII which was characterized by¹H NMR, HPLC and mass spectrometry (m/z: 463 (M⁺+1)).

EXAMPLE 68 (COMPOUND XIII)

COMPOUND XII (45 mg, 0.097 mmol) was diluted into toluene (1.5 mL),cooled to −78° C. and treated with DIBAL-H (1 M in toluene, 0.107 mL,0.107 mmol). The resulting reaction mixture was maintained at −78° C.for 1 h., and then quenched with aqueous potassium sodium tartrate(0.060 mL), warmed to 23° C., filtered through celite, washed with Et₂O,the solution then dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by preparative thin layerchromatography (SiO₂, acetone-hexane) to provide 20 mg of COMPOUND XIIIwhich was used directly in EXAMPLE 69 below.

EXAMPLE 69 (COMPOUND XIV)

COMPOUND XIII (25 mg, 0.062 mmol) was diluted into THF (1 mL) andtreated with NaBH₄ (24 mg, 0.62 mmol). The resulting reaction mixturewas maintained at 23° C. for 1 h., partitioned between aqueous sodiumbicarbonate and methylene chloride, dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified by preparative thinlayer chromatography (SiO₂, 5% MeOH-chloroform) to provide 15 mg ofCOMPOUND XIV which was characterized as two isomers by ¹H NMR, HPLC andmass spectrometry (m/z: 406 (M⁺+1)).

EXAMPLE 70 (COMPOUND XV)

COMPOUND XIII (20 mg, 0.050 mmol) was diluted into CH₂Cl₂ (1 mL) andtreated with dimethylamine (0.037 mL, 0.074 mmol), DIEA (0.030 mL, 0.150mmol) and Na(OAc)₃BH (21 mg, 0.10 mmol). The resulting reaction mixturewas maintained at 23° C. for 4 h., partitioned between aqueous sodiumbicarbonate and methylene chloride, dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was purified by preparative thinlayer chromatography (SiO₂, 5% MeOH-chloroform) to provide 21 mg ofCOMPOUND XV which was characterized by ¹H NMR, HPLC and massspectrometry (m/z: 433 (M⁺+1)).

EXAMPLES 71–78

The following indazoles were prepared under conditions similar to thosedescribed in EXAMPLES 65–70 as shown in Scheme 7 and were characterizedby ¹H NMR, HPLC and mass spectrometry. The TABLE 3 below for EXAMPLES65–70 refer to the following general chemical formula:

TABLE 3

EX. R Group Z Group MS (m/z) 71 NHCH₂C(CH₃)₃ CON(OMe)Me 481 (M⁺+1) 72NHCH₂C(CH₃)₃ CHO 422 (M⁺+1) 73 NHCH₂C(CH₃)₃ CH₂OH 424 (M⁺+1) 74NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 451 (M⁺+1) 75

CON(OMe)Me 515 (M⁺+1) 76

CHO 456 (M⁺+1) 77

CH₂OH 458 (M⁺+1) 78

CH₂N(CH₃)₂ 485 (M⁺+1)

INTERMEDIATE COMPOUND XVI

To a solution of Me(MeO)NH—HCl (26.8 g, 275 mmol), EDCI (10.6 g, 54.9mmol) and DIEA (67 mL, 384.6 mmol) in 1:4 DMF-CH₂Cl₂ (75 mL) at 0° C.was added 3-nitro-4-aminobenzoic acid (10 g, 54.9 mmol) in 1:1DMF-CH₂Cl₂ (50 mL). The resulting reaction mixture was warmed to 23° C.,maintained 15 h., partitioned between NH₄Cl_((aq)) and CH₂Cl₂, theorganic phase washed with NaHCO_(3(aq)), then dried over anhydroussodium sulfate and concentrated in vacuo. The crude material waspurified by flash column chromatography (SiO₂, acetone-hexane) toprovide 8.9 g of product which was characterized by ¹H NMR, HPLC andmass spectrometry (m/z: 226 (M⁺+1)).

This material (10 g, 44.4 mmol) was then diluted into dioxane (100 mL),2-(methylthio)-4-chloropyrimidine (8.6 g, 53 mmol) was added, followedby cesium carbonate (25.7 g, 133 mmol), Pd₂(dba)₃ (900 mg) and XANTHPHOS(1 g), and the resulting reaction mixture was heated at 90° C. for 15 h.The reaction mixture was partitioned between water and methylenechloride, the organic phase dried over anhydrous sodium sulfate,concentrated in vacuo and the solid purified by recrystallization fromacetone-hexane (primary) and then ethyl acetate-hexane (secondary) toprovide 10.3 g of INTERMEDIATE COMPOUND XVI which was characterized by¹H NMR, HPLC and mass spectrometry (m/z: 350 (M⁺+1)).

INTERMEDIATE COMPOUND XVII

INTERMEDIATE COMPOUND XVI (1 g, 3.13 mmol) was diluted into CH₂Cl₂ (75mL) and treated with Pd—C (300 mg), vacuum-purged with hydrogen gas viaa balloon, and the resulting reaction mixture maintained at 23° C. for15 h under 1 atm of hydrogen. The reaction mixture was filtered throughcelite, and the residue purified by flash column chromatography (SiO₂,acetone-hexane) to provide 980 mg of product. This material (2.7 g, 9.2mmol) was diluted into nitrobenzene (15 mL), 2,4-difluorobenzaldehyde(1.4 g, 10.1 mmol) was added, and the resulting reaction mixture washeated at 175° C. for 15 h. The reaction mixture was loaded directly onsilica gel and purified by flash column chromatography (SiO₂,acetone-hexane) to provide 1 g of product and 1.6 g of intermediateimine. This imine was recycled through the reaction conditions andpurified to provide an additional 1.1 g of product (total 2.1 g ofINTERMEDIATE COMPOUND XVII) which was characterized by ¹H NMR, HPLC andmass spectrometry (m/z: 442 (M⁺+1)).

EXAMPLE 81 (COMPOUND XVIII)

INTERMEDIATE COMPOUND XVII (2 g, 4.54 mmol) was diluted into CH₂Cl₂ (15mL) and methanol (150 mL), and treated with a solution of oxone (5.6 g,9.1 mmol) in water (75 mL). The resulting reaction mixture wasmaintained at 23° C. for 15 h., and the reaction mixture was filtered toremove the precipitate, the filtrate evaporated and then partitionedbetween aqueous sodium bicarbonate and methylene chloride, the organicphase dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by flash column chromatography (SiO₂,acetone-hexane) to provide 600 mg of sulfone. This material (50 mg,0.106 mmol) was diluted into DMSO (1 mL) and treated with(S)-(−)-alpha-methylbenzylamine (64 mg, 0.528 mmol). The resultingreaction mixture was maintained at 80° C. for 15 h., and the reactionmixture partitioned between water and methylene chloride, the organicphase dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography (SiO₂,acetone-hexane) to provide 48 mg of COMPOUND XVIII which wascharacterized by ¹H NMR, HPLC and mass spectrometry (m/z: 515 M⁺+1)).

EXAMPLE 82 (COMPOUND XIX)

Representative Procedure from Scheme 8. The starting methoxy methylamide (60 mg, 0.12 mmol) was diluted into toluene (1.5 mL), cooled to−78° C. and treated with DIBAL-H (1 M in toluene, 0.142 mL, 0.142 mmol).The resulting reaction mixture was maintained at −78° C. for 1 h., andthen quenched with aqueous potassium sodium tartrate (0.022 mL), warmedto 23° C., filtered through celite, washed with Et₂O, the solution thendried over anhydrous sodium sulfate and concentrated in vacuo. Theproduct (COMPOUND XIX) (56 mg) was used directly in EXAMPLE 83 togenerate COMPOUND XX below.

EXAMPLE 83 (COMPOUND XX)

Representative Procedure from Scheme 8. COMPOUND XIX (25 mg, 0.055 mmol)was diluted into THF (1 mL) and treated with NaBH₄ (21 mg, 0.55 mmol).The resulting reaction mixture was maintained at 23° C. for 1 h.,partitioned between aqueous sodium bicarbonate and methylene chloride,dried over anhydrous sodium sulfate and concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography (SiO₂, 5%MeOH-chloroform) to provide 15 mg of COMPOUND XX which was characterizedby ¹H NMR, HPLC and mass spectrometry (m/z: 456 (M⁺+1)).

EXAMPLE 84 (COMPOUND XXI)

Representative Procedure from Scheme 8. The requisite aldehyde (30 mg,0.074 mmol) was diluted into CH₂Cl₂ (1 mL) and treated withdimethylamine (0.056 mL, 0.117 mmol), DIEA (0.042 mL, 0.222 mmol) andNa(OAc)₃BH (31 mg, 0.15 mmol). The resulting reaction mixture wasmaintained at 23° C. for 4 h., partitioned between aqueous sodiumbicarbonate and ethyl acetate, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by preparative thinlayer chromatography (SiO₂, 10% MeOH-chloroform) to provide 21 mg ofCOMPOUND XXI which was characterized by ¹H NMR, HPLC and massspectrometry (m/z: 433 (M⁺+1)).

EXAMPLES 85–125

The following benzimidazoles were prepared under conditions similar tothose described in EXAMPLES 79–84 as shown in Scheme 8 and werecharacterized by ¹H NMR, HPLC and mass spectrometry. The following TABLE4 refers to the following chemical structure:

TABLE 4

EX Ar Group R Group Z Group Ms (m/z) 85 4-Fluorophenyl NHCH₂C(CH₃)₃CH₂OH 406 (M⁺+1) 86 4-Fluorophenyl NHCH₂C(CH₃)₃ CON(OMe)Me 463 (M⁺+1) 873-Trifluoromethylphenyl NHCH₂C(CH₃)₃ CON(OMe)Me 513 (M⁺+1) 883-Trifluoromethylphenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 483 (M⁺+1) 892-Chlorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 450 (M⁺+1) 902-Chloro-4-fluorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 467 (M⁺+1) 912,4-Difluorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 451 (M⁺+1) 922,4-Difluorophenyl NHCH₂C(CH₃)₃ CH₂OH 424 (M⁺+1) 93 2,4-DifluorophenylNHCH₂C(CH₃)₃ CON(OMe)Me 481 (M⁺+1) 94 2,4-Difluorophenyl NHCH₂C(CH₃)₃

534 (M⁺+1) 95 2,4-Difluorophenyl NHCH₂C(CH₃)₃

563 (M⁺+1) 96 2,4-Difluorophenyl NHCH₂C(CH₃)₃

504 (M⁺+1) 97 2,4-Difluorophenyl NHCH₂C(CH₃)₃

493 (M⁺+1) 98 2,4-Difluorophenyl NHCH₂C(CH₃)₃

532 (M⁺+1) 99 2,4-Difluorophenyl NHCH₂C(CH₃)₃ CH₂NH(CH₂)₂OCH₃ 481 (M⁺+1)100 2,4-Difluorophenyl NHCH₂C(CH₃)₃ CH₂NH(CH₂)₂N(CH₃)₂ 494 (M⁺+1) 1012,4-Difluorophenyl NH(CH₂)₃OCH₃ CON(OMe)Me 483 (M⁺+1) 1022,4-Difluorophenyl

CON(OMe)Me 515 (M⁺+1) 103 2,4-Difluorophenyl

CON(OMe)Me 531 (M⁺+1) 104 2,4-Difluorophenyl NHCH₂C(CH₃)₂CH₂OH CH₂OH 440(M⁺+1) 105 2,4-Difluorophenyl

CON(OMe)Me 495 (M⁺+1) 106 2,4-Difluorophenyl

CH₂N(CH₃)₂ 485 (M⁺+1) 107 2,4-Difluorophenyl

527 (M⁺+1) 108 2,4-Difluorophenyl

538 (M⁺+1) 109 2,4-Difluorophenyl NHCH₂C(CH₃)₂CH₂OH CH₂N(CH₃)₂ 467(M⁺+1) 110 2,4-Difluorophenyl NH(CH₂)₃OCH₃

495 (M⁺+1) 111 2,4-Difluorophenyl NH(CH₂)₃OCH₃ CH₂N(CH₃)₂ 453 (M⁺+1) 1122,4-Difluorophenyl NHCH₂C(CH₃)₂CH₂OH CON(OMe)Me 497 (M⁺+1) 1132,4-Difluorophenyl NH(CH₂)₄OH CH₂N(CH₃)₂ 453 (M⁺+1) 1142,4-Difluorophenyl

CH₂N(CH₃)₂ 485 (M⁺+1) 115 2,4-Difluorophenyl

CH₂N(CH₃)₂ 501 (M⁺+1) 116 2,4-Difluorophenyl

CH₂N(CH₃)₂ 463 (M⁺+1) 117 2,4-Difluorophenyl

CH₂N(CH₃)₂ 465 (M⁺+1) 118 2,4-Difluorophenyl

CH₂N(CH₃)₂ 515 (M⁺+1) 119 2,4-Difluorophenyl

CH₂N(CH₃)₂ 530 (M⁺+1) 120 2,4-Difluorophenyl

CH₂N(CH₃)₂ 499 (M⁺−15) 121 2,4-Difluorophenyl

CH₂N(CH₃)₂ 564 (M⁺+1) 122 2,4-Difluorophenyl

CH₂N(CH₃)₂ 510 (M⁺+1) 123 2,4-Difluorophenyl

CH₂N(CH₃)₂ 543 (M⁺+1) 124 2,4-Difluorophenyl

CH₂N(CH₃)₂ 543 (M⁺+1) 125 2,4-Difluorophenyl NH(CH₂)₃CO₂H CH₂N(CH₃)₂ 467(M⁺+1)

INTERMEDIATE COMPOUND 106 was prepared by the literature procedure: J.Med. Chem. 1999, 42 2180–2190.

INTERMEDIATE COMPOUND 107 was prepared from INTERMEDIATE COMPOUND 106(10 g, 32 mmol) using a procedure like that described for thepreparation of INTERMEDIATE COMPOUND 8 above in Scheme 2. Yellow oil,(9.91 g).

¹H NMR (CDCl₃, 300 MHz) δ 8.61 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 8.22 (d,J=8.2 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.66 (t, J=7.9 Hz, 1), 7.41 (d,J=5.2 Hz, 1H), 6.19 (s, 1H), 2.52 (s, 3H).

INTERMEDIATE COMPOUNDS 108 and 109

An ethanol (150 mL) solution of INTERMEDIATE COMPOUND 107 (5.0 g, 13mmol) and 2-aminopyrimidine (5.1 g, 53 mmol) was heated at reflux for 18h under argon. The contents of the reaction flask were cooled andconcentrated in vacuo. Water and sat. NaHCO₃ (aq.) were added and theresulting mixture was extracted with methylene chloride (3×). Thecombined organic extracts were dried with Na₂SO₄ (anh.), filtered, andconcentrated in vacuo. The crude product was subjected to flash columnchromatography (methylene chloride methanol 99:1). Two productsco-eluted. Product containing fractions were combined and the solventremoved in vacuo to give a tan solid which was triturated with ether andfiltered to give a white solid, INTERMEDIATE COMPOUND 108 (1.24 g). Thefiltrate was concentrated in vacuo and rechromatographed using hexaneethyl acetate 30:70 to give after evaporation a tan foam, INTERMEDIATECOMPOUND 109 (2.32 g).

INTERMEDIATE COMPOUND 108: ¹H NMR (CDCl₃, 300 MHz) δ 8.68 (m, 1H), 8.58(d, 1H), 8.15 (m, 1H), 8.02 (d, 1H), 7.80 (s, br, 2H), 7.70 (m, 2H),6.92 (m, 1H), 1.84 (s, 3H).

INTERMEDIATE COMPOUND 109: ¹H NMR (CDCl₃, 300 MHz) δ 9.88 (dd, J=6.9,2.1 Hz, 1H), 8.74 (dd, J=4.1, 2.1 Hz, 1H), 8.36 (d, J=5.4 Hz, 1H), 8.06(s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.8 Hz, 111), 7.59 (t, J=7.7Hz, 1H), 7.09 (dd, J=6.9, 3.9 Hz, 1H), 6.88 (d, J=5.4 Hz, 1H), 2.65 (s,3H).

INTERMEDIATE COMPOUND 110 was prepared using INTERMEDIATE COMPOUND 108by a procedure like that described for the preparation of INTERMEDIATECOMPOUND 10 above in Scheme 2.

¹H NMR (CDCl₃, 300 MHz) δ 9.00 (d, 1H), 8.75 (m, 1H), 8.56 (d, 1H), 8.18(m, 1H), 2.73 (s, 3H).

EXAMPLE 126 was prepared using INTERMEDIATE COMPOUND 110 by a procedurelike that described above for the preparation of COMPOUND 11 (EXAMPLEA01).

MS (M+H) m/z 461

INTERMEDIATE COMPOUND 112 was prepared using INTERMEDIATE COMPOUND 109by a procedure like that described for the preparation of INTERMEDIATECOMPOUND 10 above in Scheme 2.

MS (M+H) m/z 420

EXAMPLES 127–130 in TABLE 5 below were prepared by reacting INTERMEDIATECOMPOUND 112 with an amine using a procedure like that described abovefor the preparation of EXAMPLE A01 (COMPOUND 11).

TABLE 5

EXAMPLE R MS (M+H) m/z 127

461 128

425 129

361 130

495

INTERMEDIATE COMPOUND 117 was prepared from INTERMEDIATE COMPOUND 107and 2-aminopyridine using a procedure like that described for thepreparation of INTERMEDIATE COMPOUND 9.

¹H NMR (CDCl₃, 300 MHz) δ 9.55 (m, 1H), 8.32 (d, 1H), 8.00 (s, 1H), 7.00(m, 1H), 6.80 (d, 1H), 2.62 (s, 3H).

INTERMEDIATE COMPOUND 118 was prepared using INTERMEDIATE COMPOUND 117by a procedure like that described for the preparation of INTERMEDIATECOMPOUND 10.

¹H NMR (CDCl₃, 300 MHz) δ 9.90 (d, 1H), 8.55 (d, 1H), 7.99 (s, 1H), 7.28(m, 1H), 7.15 (m, 1H), 3.42 (s, 3H).

EXAMPLES 131–134 in TABLE 6 were prepared by reacting INTERMEDIATECOMPOUND 118 with an amine using a procedure like that described for thepreparation of EXAMPLE A01 (COMPOUND 11).

TABLE 6

¹H NMR (CDCl₃, MS (M+H) EXAMPLE R 300MHz) δ m/z 131

460 132

8.14(m, 1H), 8.03(s, br,1H), 7.75–7.65(m, 2H),7.55(m, 1H), 7.36(m, 1H),133

9.50(d, 1H), 8.15(d, 1H),8.04(s, 1H), 7.85(d, 1H),6.94(m, 1H), 6.40(d,1H), 134

9.45(d, 1H), 8.15(d, 1H),8.03(s, 1H), 7.85(d, 1H),7.75–7.65(m, 2H),7.53(m,1H), 7.39(m, 1H), 6.95(m,

An ethyl acetate (100 mL) solution of EXAMPLE 134 (0.50 g, 1.02 mmol)was cooled in an ice bath with stirring. Hydrogen chloride gas wasbubbled through the solution for 5 min. After 15 min. the solvent wasremoved in vacuo and the remaining solid was recrystallized fromacetonitrile to give EXAMPLE 135 as a solid (84 mg).

¹H NMR (DMSO-d₆, 300 MHz) δ 8.33 (d, 1H), 8.09–7.95 (m, 5H), 7.83 (m,1H), 7.54 (m, 1H), 3.70 (m, 2H), 3.11 (m, 2H).

Scheme 12:

EXAMPLES 136–138 in TABLE 7 were prepared using a synthetic sequencelike that described for the preparation of compounds in TABLE 6 except2-amino-4-picoline was used in the place of 2-aminopyridine in theinitial condensation reaction with compound INTERMEDIATE COMPOUND 107.

TABLE 7

¹H NMR (CDCl₃, MS (M+H) EXAMPLE R 300MHz) δ m/z 136

8.10(d, 1H), 7.95(s, 1H),7.80(d, 1H), 7.64(m, 1H),7.53–7.30(m, 8H),6.38(m, 137

9.40(m, 1H), 8.13(d, 1H),8.03(s, 1H), 7.85(d, 1H),7.65(d, 1H), 7.52(m,2H),6.79(m, 1H), 6.40(d, 1H), 138

9.37(d, 1H), 8.10(d, 1H),8.00(s, 1H), 7.83(m, 1H),7.65(m, 1H), 7.50(m,2H),6.79(m, 1H), 6.40(d, 1H),

EXAMPLE 139 was prepared using a synthetic sequence like that describedfor the preparation of the compounds in TABLE 6 except2-amino-5-picoline was used in the place of 2-aminopyridine in theinitial condensation reaction with INTERMEDIATE COMPOUND 107.

¹H NMR (CDCl₃, 300 MHz) δ 8.95 (s, br, 1H), 8.11 (d, 1H), 8.00 (s, 1H),7.81 (d, 1H), 7.65–7.55 (m, 2H), 7.52–7.42 (m, 3H), 7.38 (m, 1H), 7.29(m, 1H), 7.15 (m, 1H), 6.41 (d, 1H), 5.81 (m, 1H), 5.30 (m, 1H), 2.20(s, br, 3H), 1.61 (d, 3H).

EXAMPLE 140 was prepared using a synthetic sequence like that describedfor the preparation of compounds in TABLE 6 except 2-amino-3-picolinewas used in the place of 2-aminopyridine in the initial condensationreaction with compound INTERMEDIATE COMPOUND 107.

MS (M+) m/z 474

INTERMEDIATE COMPOUND 129 was prepared using a synthetic sequencesimilar to that described for the preparation of INTERMEDIATE COMPOUND 5except 6-aminonicotinic acid was used in the place of INTERMEDIATECOMPOUND 3.

¹H NMR (CD₃OD, 300 MHz) δ 7.85 (m, 1H), 7.48 (m, 1H), 6.59 (m, 1H), 4.42(s, 2H).

EXAMPLE 141 was prepared using a synthetic sequence like that describedin Scheme 10 for the preparation of EXAMPLE 127 except INTERMEDIATECOMPOUND 129 was used in the place of 2-aminopyrimidine in thecondensation reaction with compound INTERMEDIATE COMPOUND 107.

¹H NMR (CDCl₃, 300 MHz) δ 9.10 (m, 1H), 8.15 (d, 1H), 8.00 (s, 1H), 7.82(d, 1H), 7.65 (m, 1H), 7.54–7.30 (m, 7H), 6.42 (d, 1H), 5.60 (m, 1H),5.25 (m, 1H), 4.45 (s, br, 1H), 1.62 (d, 3H).

Molecular sieves (4 Å) were added to a methylene chloride (3 mL)solution of EXAMPLE 141 (50 mg, 0.10 mmol) under argon. After 5 min4-methylmorpholine N-oxide (18 mg, 0.15 mmol) and tetrapropylammoniumperruthenate (4 mg, 0.10 mmol) were added. After 1 h the contents of thereaction flask were subjected to flash column chromatographypurification (hexane ethyl acetate 1:1) to give EXAMPLE 142 as a whitesolid (28 mg).

MS (M+H) m/z 488

EXAMPLE 143 was prepared by reductive amination of EXAMPLE 142 withbenzylamine using a procedure like that described for the preparation ofcompound 14 (EXAMPLE A04).

MS (M+H) m/z 579

EXAMPLE 144 was prepared using a synthetic sequence like that describedin Scheme 10 for the preparation of EXAMPLE 127 except methyl6-aminonicotinate was used in the place of 2-aminopyrimidine in thecondensation reaction with compound INTERMEDIATE COMPOUND 107.

MS (M+H) m/z 518

A solution of lithium hydroxide (7 mg, 0.29 mmol) in a minimum amount ofwater was added to a THF (1.5 mL) solution of EXAMPLE 144 (140 mg, 0.27mmol) under argon. After 1.5 h THF was removed in vacuo and the contentsof the reaction flask were acidified with 1N hydrochloric acid. A solidappeared which was isolated by vacuum filtration. Toluene was added tothe solid, stirred, then removed in vacuo. The remaining solid wastriturated with ether and isolated to give EXAMPLE 145 (60 mg).

MS (M+H) m/z 504

Triethylamine (0.122 mL, 0.88 mmol) was added with stirring to aN,N-dimethylformamide (5 mL) solution of EXAMPLE 145 (400 mg, 0.794mmol), 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (167mg, 0.874 mmol), 1-hydroxy-7-azabenzotriazole (118 mg, 0.874 mmol), andpiperidine (0.087 mL, 0.874 mmol) under argon. After 48 h the contentsof the reaction flask were poured into water and the resulting mixturewas extracted with ethyl acetate (3×). The combined organic extractswere dried with Na₂SO₄ (anh.), filtered, and concentrated in vacuo. Thecrude product was subjected to flash column chromatography (ethylacetate) to give after evaporation a yellow oil, (360 mg).

MS (M+H) m/z 571

EXAMPLE 147 was prepared from EXAMPLE 145 using a procedure like thatdescribed for compound EXAMPLE 146 except replacing piperidine withN,N-dimethylethylenediamine.

MS (M+H) m/z 574

Diphenylphophoryl azide (0.130 mL, 0.596 mmol) and benzyl alcohol (0.093mL, 0.891 mmol) were added to a toluene (5 mL) solution of 134 (150 mg,0.297 mmol) and the resulting solution was heated at reflux 24 h. Thecontents of the reaction flask were cooled and the solvent removed invacuo. The remaining residue was subjected to flash columnchromatography (ethyl acetate hexane 30:70 then 50:50) to give afterevaporation EXAMPLE 148 (96 mg).

MS (M+H) m/z 609

EXAMPLE 149 was prepared from EXAMPLE 141 using a procedure like thatdescribed for the preparation of EXAMPLE A02 (COMPOUND 12).

MS (M+m) m/z 515

EXAMPLE 150 was prepared from EXAMPLE 149 using a procedure like thatdescribed for the preparation of EXAMPLE A03 (COMPOUND 13).

MS (M+H) m/z 489

EXAMPLE 151 was prepared from EXAMPLE 150 by reductive amination withformaldehyde using a procedure like that described for the preparationof EXAMPLE A04 (COMPOUND 14).

MS (M+H) m/z 517

A methylene chloride (3 mL) solution of EXAMPLE 150 (25 mg, 0.05 mmol)was cooled in an ice bath under argon. Methanesulfonyl chloride (0.020mL, 0.263 mmol) and triethylamine (0.041 mL, 0.297 mmol) were added andthe reaction was allowed to warm to room temperature. The solvent wasremoved in vacuo and the remaining residue was subjected to flash columnchromatography (ethyl acetate) to afford after evaporation a white solid141 (15 mg).

MS (M+H) m/z 567

A methanol (250 mL) solution of 2-aminonicotinic acid (10.5 g, 76 mmol),and sulfuric acid (20 mL) was refluxed 18 h. The reaction was cooled toroom temperature and the solvent was removed in vacuo. Sat. sodiumbicarbonate (aq.) was added and the mixture was extracted with ethylacetate. The organic layer was dried with anhydrous sodium sulfate,filtered, and evaporated in vacuo to give a white solid INTERMEDIATECOMPOUND 142 (5.5 g).

¹H NMR (CD₃OD, 300 MHz) δ 8.19 (m, 2H), 7.64 (m, 1H), 3.89 (s, 3H).

INTERMEDIATE COMPOUND 143 was prepared using a synthetic sequence likethat described in Scheme 10 for the preparation of INTERMEDIATE COMPOUND112 except INTERMEDIATE COMPOUND 142 was used in the place of2-aminopyrimidine in the condensation reaction with compoundINTERMEDIATE COMPOUND 107.

¹H NMR (CDCl₃, 300 MHz) δ 10.10 (m, 1H), 8.58 (d, 1H), 8.25 (m, 1H),8.00 (s, 1H), 7.85 (m, 1H), 7.76 (m, 1H), 7.63 (m, 1H), 7.26 (m, 2H),4.09 (s, 3H), 3.43 (s, 3H).

EXAMPLES 153 (COMPOUND 144) AND 154 (COMPOUND 145)

S-(−)-α-Methylbenzylamine (15 mL) and INTERMEDIATE COMPOUND 143 (2.61 g,5.48 mmol) were combined under argon and heated at 60° C. for 1 h.Cooled, added citric acid (aq.) and extracted with ethyl acetate. Driedthe organic layer with anhydrous sodium sulfate and removed solvent invacuo to give a yellow solid. Flash column chromatography (ethyl acetatehexane 25:75) followed by reverse phase preparative HPLC afforded, afterevaporation, EXAMPLES 153 and EXAMPLES 154.

EXAMPLE 153

MS (M+H) m/z 518

EXAMPLE 154

MS (M+H) m/Z 607

Lithium aluminum hydride solution (1 mL, 1M) was slowly added to a THFsolution of EXAMPLE 154 (300 mg, 0.580 mmol) under argon at roomtemperature. After 18 h the reaction was quenched with water and sodiumhydroxide (aq.). Magnesium sulfate was added and the mixture wasfiltered. The filtrate was evaporated in vacuo to give a red oil. Flashcolumn chromatography gave EXAMPLE 155 after evaporation as a whitesolid (60 mg).

MS (M+H) m/z 490

EXAMPLE 156 was prepared from EXAMPLE 155 using a procedure like thatdescribed for the preparation of EXAMPLE A02 (COMPOUND 12).

EXAMPLE 157 was prepared from EXAMPLE 156 using a procedure like thatdescribed for the preparation of EXAMPLE A03 (COMPOUND 13).

Combustion analysis for EXAMPLE 157: Calculated forC₂₇H₂₃N₆F₃.0.05H₂O.0.45MeOH C 65.43%; H 4.98%; N 16.68%. Found: C65.43%; H 4.62%; N 16.61%.

EXAMPLE 158 was prepared from EXAMPLE 157 using a procedure like thatdescribed for the preparation of EXAMPLE 152.

MS (M+H) m/z 567

EXAMPLE 159 was prepared from EXAMPLE 153 using a procedure like thatdescribed for the preparation of compound EXAMPLE 145.

Combustion analysis for EXAMPLE 159: Calculated forC₂₇H₂₀N₅O₂F₃.0.10H₂O.1.95TFA C 51.00%; H 3.07%; N 9.63%. Found: C51.00%; H 3.04%; N 9.62%.

A neat solution of COMPOUND 144 in N,N-dimethylethylenediamine washeated at 80° C. under argon for 2 h. The contents of the reaction flaskwere cooled to room temperature and acetonitrile/water/methanol wasadded. The resulting solution was subjected to reverse phase preparativeHPLC to give after evaporation COMPOUND 151.

MS (M+H) m/z 574

A neat solution of 4-amino-1-BOC-piperidine (300 mg, 1.5 mmol) and 144(50 mg, 0.1 mmol) was heated at 80° C. under argon for 18 h. cooled toroom temperature and added ethyl acetate and water. The organic layerwas dried with anhydrous sodium sulfate, filtered and concentrated invacuo. Methylene chloride (4 mL) and trifluoroacetic acid (4 mL) wereadded. After 3 h the solvents were evaporated in vacuo and the remainingresidue was subjected to reverse phase preparative HPLC to give afterevaporation a yellow solid, 152 (10 mg, 17%).

MS (M+H) m/z 586

INTERMEDIATE COMPOUND 153 was prepared using a synthetic sequence likethat described in Scheme 10 for the preparation of INTERMEDIATE COMPOUND112 except INTERMEDIATE COMPOUND 5 was used in the place of2-aminopyrimidine in the condensation reaction with compoundINTERMEDIATE COMPOUND 107.

INTERMEDIATE COMPOUND 153: ¹H NMR (CDCl₃, 300 MHz) δ 9.81 (d, 1H), 8.55(d, 1H), 7.95 (s, 1H), 7.80 (m, 3H), 7.65 (m, 1H), 7.25 (m, 1H), 7.11(m, 1H), 4.86 (s, 2H), 3.41 (m, 2H).

EXAMPLE 162 was prepared from INTERMEDIATE COMPOUND 153 using aprocedure like that described for the preparation of EXAMPLE A01(COMPOUND 11) except 3-ethoxypropylamine was used in the place ofs-(−)-α-methylbenzylamine.

MS (M+H) m/z 472

EXAMPLE 163 was prepared from INTERMEDIATE COMPOUND 153 using aprocedure like that described for the preparation of EXAMPLE A01(COMPOUND 11) except N,N-ethylenediamine was used in the place ofs-(−)-α-methylbenzylamine.

MS (M+H) m/z 457

EXAMPLE 164 (COMPOUND 156) AND INTERMEDIATE COMPOUND 157

S-(−)-α-Methylbenzylamine (5 mL) was added to an isopropanol (15 mL)solution of INTERMEDIATE COMPOUND 153 (1.90 g, 4.24 mol) under argon andthe resulting mixture was heated at 60° C. 18 h. The contents of thereaction flask were cooled to room temperature and treated with citricacid (aq.). The pH was adjusted to 4.5 with NaOH (aq.) and extractedwith ethyl acetate (2×). The combined organic extracts were dried withanhydrous sodium sulfate, filtered, and the filtrate concentrated invacuo to give a red oil. Flash column chromatography (ethyl acetatehexane 40:60 then 70:30) to give two portions after evaporation: 1. 156(349 mg) and 2. A mixture (610 mg) of 156 and 157.

156: ¹H NMR (CDCl₃, 300 MHz) δ 8.11 (d, 1H), 7.95 (s, 1H), 7.80 (d, 1H),7.70–7.30 (m, 10H), 6.36 (d, 1H), 5.68 (m, 1H), 5.16 (m, 1H), 4.72 (m,2H), 1.63 (d, 3H).

EXAMPLE 166 (COMPOUND 158) AND INTERMEDIATE COMPOUND 159

Diphenylphophoryl azide (0.0.323 mL, 1.50 mmol) and1,8-diazabicyclo[4.5.0]undec-7-ene (0.224 mL, 1.50 mmol) were added to atoluene (5 mL) solution of EXAMPLE 141 (115 mg, 0.235 mmol) under argon.After 18 h the reaction was poured into water and extracted (3×) withethyl acetate. The combined organic portions were dried with Na₂SO₄(anh.), filtered, and concentrated in vacuo. The crude product wassubjected to flash column chromatography (ethyl acetate hexane 10:90then 20:80) to give after evaporation two products: 1. White solid, 158(100 mg) and 2. Solid, 159 (38 mg).

158: ¹HNMR (CDCl₃, 300 MHz) δ 8.15 (d, 1H), 7.97 (s, 1H), 7.83 (d, 1H),7.66 (d, 1H), 7.59–7.33 (m, 9H), 5.70 (m, 1H), 5.16 (m, 1H), 4.40 (s,2H), 1.65 (d, 3H).

159: ¹H NMR (CDCl₃, 300 MHz) δ 9.60 (d, 1H), 8.32 (d, 1H), 8.00 (s, 1H),7.82 (d, 1H), 7.70 (m, 2H), 7.57 (m, 1H), 6.95 (m, 1H), 6.75 (m, 1H),5.39 (m, 1H), 4.50 (s, 2H), 1.50 (d, 6H).

INTERMEDIATE COMPOUND 160 was prepared from INTERMEDIATE COMPOUND 159using a procedure like that described for the preparation of EXAMPLE A03(COMPOUND 13).

MS (M+H) m/z 428

EXAMPLE 169 (COMPOUND 161)

EXAMPLE 169 was prepared from EXAMPLE 166 using a procedure like thatdescribed for the preparation of EXAMPLE A03 (COMPOUND 13).

MS (M+H) m/z 489

EXAMPLE 170 was prepared from EXAMPLE 169 using a procedure like thatdescribed for the preparation of EXAMPLE 152 (COMPOUND 141).

MS (M+H) m/z 567

EXAMPLE 171 was prepared from EXAMPLE 169 by reductive amination using aprocedure like that described for the preparation of EXAMPLE A04(COMPOUND 14).

MS (M+H) m/z 517

EXAMPLE 172 was prepared from EXAMPLE 169 by reductive amination using aprocedure like that described for the preparation of EXAMPLE A04(COMPOUND 14) except formaldehyde (aq.) was replaced with acetone.

MS (M+H) m/z 531

EXAMPLE 173 was prepared from EXAMPLE 169 by reductive amination using aprocedure like that described for the preparation of EXAMPLE A04 exceptformaldehyde (aq.) was replaced with ethyl formate.

MS (M+H) m/z 517

A THF solution of EXAMPLE 173 (61 mg, 0.12 mmol) under argon was treatedwith 1M borane-THF solution (0.59 mL, 0.59 mmol) and stirred at roomtemperature. After 18 h, 2M hydrochloric acid was added and after 2 hthe reaction was made basic with sat. sodium bicarbonate (aq.). Theresulting mixture was extracted with ethyl acetate (2×). The combinedorganic extracts were dried with anhydrous sodium sulfate, filtered, andevaporated in vacuo to give a yellow oil. Flash column chromatography(methylene chloride methanol ammonium hydroxide 95:5:0.5 gave afterevaporation a yellow solid of EXAMPLE 173 (31 mg).

MS (M+H) m/z 503

Compounds in TABLE 8 below were prepared by reacting EXAMPLE 169 with acarboxylic acid using a coupling procedure like that described for thepreparation of EXAMPLE 146.

TABLE 8

EXAMPLE R MS (M+H) m/z 175

653 176

557 177

629 178

697 179

596 180

625

EXAMPLE 181 was prepared using a synthetic sequence like that describedin Scheme 10 for the preparation of EXAMPLE 127 except INTERMEDIATECOMPOUND 4 was used in the place of 2-aminopyrimidine in thecondensation reaction with compound INTERMEDIATE COMPOUND 107.

MS (M+M) m/z 532

EXAMPLE 182 was prepared from EXAMPLE 181 using a procedure like thatdescribed for the preparation of EXAMPLE 145.

¹H NMR (CD₃OD, 300 MHz) δ 8.18 (s, 1H), 8.10 (d, 1H), 7.90 (s, 1H), 7.85(m, 1H), 7.75 (m, 10), 7.65 (m, 1H), 7.48–7.25 (m, 7H), 6.30 (d, 2H),1.60 (d, 3H).

Compounds in TABLE 9 below were prepared by reacting EXAMPLE 182 with anamine using a coupling procedure like that described for the preparationof EXAMPLE 146.

TABLE 9

EXAMPLE R MS (M+H) m/z 183

571 184

589 185

531 186

472 187

625

Other EXAMPLES of the invention are shown in the following TABLE 10.These EXAMPLES are made similarly to the compounds and Schemes shownabove.

TABLE 10 Example M+1 H-NMR: (400MHz) δ B001 

467.4 CDCl₃: 8.60(br, 1H), 8.38(s,1H), 8.10(d, J=5.5Hz, 1H),7.63(m, 2H),7.45(m, 6H),7.12(m, 2H), 6.53(br, 1H),6.42(d, J=5.3Hz, 1H),6.12(br, 1H),5.84(br, 1H),5.16(m, 1H), 4.56(d,J=6.3Hz, 2H), 1.63(d,J=7.0Hz, 3H) B002 

422.3 CD₃OD: 8.58(br, 1H),8.04(d, J=5.3Hz, 1H),7.56(m, 3H), 7.42(m,4H),7.28(m, 1H), 7.18(m, 2H),6.82(br, 1H), 6.27(d,J=5.3Hz, 1H), 5.11(m,1H),4.01(s, 2H), 3.68(m, 4H),2.82(m, 1H), 1.56(d,J=7.1Hz, 3H) B003 

453.3 CDCl3: 8.56(br, 1H), 8.11(d,J=5.3Hz, 1H), 7.42(m, 7H),7.24(m, 1H),7.18(m, 2H),6.66(br, 1H), 6.22(d,J=5.3Hz, 1H), 5.10(m, 1H),3.78(s, 2H),2.41(s, 3H),1.58(d, J=7.0Hz, 3H) B004 

481.3 CD3OD: 8.56(br, 1H),8.02(d, J=5.3Hz, 1H),7.56(m, 3H), 7.42(m,5H),7.28(m, 1H), 7.14(m, 2H),6.76(br, 1H), 6.28(d,J=5.3Hz, 1H), 5.12(m,1H),3.85(s, 2H), 2.88(m, 1H),1.57(d, J=7.0Hz, 3H),1.25(m, 6H) B005 

497.4 CDCl3: 8.62(br, 1H), 8.12(d,J=5.3Hz, 1H), 7.64(m, 2H),7.45(m, 6H),7.13(m, 2H),6.62(br, 1H), 6.42(d,J=5.3Hz, 1H), 5.62(m, 1H),5.18(m, 1H),3.71(t, J=5.2Hz,2H), 3.67(s, 2H), 2.70(t,J=5.3Hz, 2H), 2.34(s,3H),1.63(d, J=7.1Hz, 3H) B006 

537.4 CD3OD: 8.56(br, 1H),8.04(d, J=5.3Hz, 1H),7.57(m, 3H), 7.42(m,4H),7.26(m, 1H), 7.18(m, 2H),6.82(br, 1H), 6.28(d,J=5.3Hz, 1H), 5.12(m,1H),4.16(m, 1H), 3.80(m, 4H),2.62(m, 2H), 2.40(s, 3H),2.02(m, 4H),1.56(d,J=7.1Hz, 3H) B007 

538.5 CD3OD: 8.42(br, 1H),8.05(d, J=5.2Hz, 1H),7.52(m, 2H), 7.40(m,5H),7.24(m, 1H), 6.62(br, 1H),6.29(d, J=5.3Hz, 1H),5.10(m, 1H), 4.62(s,2H),2.97(t, J=6.6H 2H), 2.62(t,J=6.5z, 2H), 2.15(s, 6H),1.56(d, J=7.1Hz,3H) B008 

510.4 CD3OD: 8.42(br, 1H),8.01(d, J=5.2Hz, 1H),7.52(m, 2H), 7.40(m,5H),7.24(m, 1H), 6.62(br, 1H),6.21(d, J=5.3Hz, 1H),5.07(m, 1H), 4.45(s,2H),3.10(t, J=6.7Hz, 2H), 2.61(t,J=6.6Hz, 2H), 1.54(d,J=6.8Hz, 3H) B009 

495.4 CDCl3: 8.72(br, 1H), 8.10(d,J=5.3Hz, 1H), 7.61(m, 3H),7.46(m, 4H),7.36(m, 1H),7.11(m, 2H), 6.72(br, 1H),6.42(d, J=5.3Hz, 1H),5.61(br, 1H),5.20(m, 1H),3.60(br, 2H), 2.98(br, 1H),2.23(br, 3H), 1.64(d,J=7.0Hz,3H), 1.27(br, 6H) B010 

538.5 CD3OD: 8.54(br, 1H),8.03(d, J=5.1Hz, 1H),7.55(m, 2H), 7.48(s,1H),7.42(m, 4H), 7.24(m, 1H),7.18(m, 2H), 6.78(br, 1H),6.25(d, J=5.2Hz,1H),5.12(m, 1H), 3.57(s, 2H),2.42(m, 4H), 2.27(s, 6H),1.77(m, 2H),1.56(d,J=7.1Hz, 3H) B011 

574.4 CD3OD: 8.56(br, 1H),8.04(d, J=5.3Hz, 1H),7.56(m, 2H), 7.52(s,1H),7.43(m, 4H), 7.28(m, 1H),7.18(m, 2H), 6.81(br, 1H),6.30(d, J=5.2Hz,1H),5.12(m, 1H), 3.65(s, 2H),3.27(t, J=6.4Hz, 2H), 2.97(s,3H), 2.64(t,J=6.4Hz, 2H),2.31(s, 3H), 1.56(d, J=7.0Hz,3H) B012 

536.4 CD3OD: 8.58(br, 1H),8.04(d, J=5.3Hz, 1H),7.56(m, 2H), 7.52(s,1H),7.43(m, 4H), 7.28(m, 1H),7.18(m, 2H), 6.78(br, 1H),6.28(d, J=5.3Hz,1H),5.12(m, 1H), 3.60(s, 2H),3.40(m, 4H), 2.76(t, J=6.7Hz,2H), 2.47(t,J=6.7Hz, 2H),2.27(s, 3H), 2.17(m, 2H),1.57(d, J=7.1Hz, 3H) B013 

527.4 CDCl3: 8.58(br, 1H), 8.10(d,J=5.3Hz, 1H), 7.64(m, 2H),7.45(m, 6H),7.13(m, 2H),6.60(br, 1H), 6.41(d,J=5.3Hz, 1H), 5.80(br, 1H),5.12(m, 1H),3.90(s, 2H),3.74(m, 4H), 3.14(m, 1H),2.38(s, 3H), 2.20(br, 2H),1.62(d,J=7.0Hz, 3H) B014 

433.4 CD3OD: 9.62(br, 1H),8.05(d, J=5.4Hz, 1H),7.61(m, 3H), 7.21(m,3H),6.31(d, J=5.3Hz, 1H), 3.74(s,2H), 3.38(s, 2H), 2.41(s, 6H),1.01(s,9H) B015 

447.3 CD3OD: 9.61(br, 1H),8.05(d, J=5.4Hz, 1H),7.61(m, 3H), 7.21(m,3H),6.31(d, J=5.3Hz, 1H), 3.73(s,2H), 3.36(s, 2H), 2.61(m,2H), 2.34(s,3H), 1.18(t,J=7.3Hz, 3H), 1.01(s, 9H) B016 

552.3 CD3OD: 8.57(br, 1H),8.06(d, J=5.3Hz, 1H),7.57(m, 2H), 7.50(s,1H),7.42(m, 4H), 7.28(m, 1H),7.18(m, 2H), 6.71(br, 1H),6.29(d, J=5.5Hz,1H),3.91(m, 1H), 3.69(m, 2H),3.25(s, 3H), 2.99(s, 3H),2.26(s, 3H),1.58(d, J=7.0Hz,3H), 1.25(d, J=6.6Hz, 3H) B017 

564.1 CD3OD: 8.58(br, 1H),8.05(d, J=5.3Hz, 1H),7.58(m, 2H), 7.51(s,1H),7.42(m, 4H), 7.27(m, 1H),7.18(m, 2H), 6.81(br, 1H),6.29(d, J=5.3Hz,1H),5.13(m, 1H), 3.71(s, 2H),3.55(t, J=6.7Hz, 2H), 3.42(t,J=6.9Hz, 2H),3.34(s, 2H),2.36(s, 3H), 1.99(m, 2H),1.87(m, 2H), 1.57(d,J=7.0Hz, 3H)B018 

392.2 CDCl3: 9.31(d, 1H), 8.11(d,1H), 7.64(m, 3H), 7.11(m,2H), 6.92(m,1H), 6.41(d,1H), 5.26(br, 1H), 4.80(s,2H), 1.54(s, 9H) B019 

550.1 CD3OD: 8.58(br, 1H),8.04(d, J=5.3Hz, 1H),7.58(m, 2H), 7.51(s,1H),7.43(m, 4H), 7.25(m, 1H),7.18(m, 2H), 6.81(br, 1H),6.28(d, J=5.2Hz,1H),5.13(m, 1H), 4.30(m, 2H),4.04(m, 2H), 3.66(s, 2H),3.13(s, 2H),2.32(m, 5H),1.57(d, J=7.1Hz, 3H) B020 

550.1 CD3OD: 8.57(br, 1H),8.04(d, J=5.3Hz, 1H),7.57(m, 2H), 7.48(s,1H),7.43(m, 4H), 7.30(m, 1H),7.18(m, 2H), 6.70(br, 1H),6.28(d, J=5.3Hz,1H),5.12(m, 1H), 3.71(s, 2H),3.65(m, 3H), 2.94(s, 6H),1.57(d, J=7.0Hz,3H) B021 

497.1 CD3OD: 8.48(br, 1H),8.02(d, J=5.3Hz, 1H),7.54(m, 2H), 7.41(m,5H),7.23(m, 1H), 7.17(m, 2H),6.61(br, 1H), 6.23(d,J=5.5Hz, 1H), 5.07(m,1H),4.34(s, 2H), 3.72(s, 3H),1.55(d, J=7.1Hz, 3H) B022 

580.2 CD3OD: 8.60(br, 1H),8.05(d, J=5.6Hz, 1H),7.57(m, 2H), 7.53(s,1H),7.43(m, 4H), 7.28(m, 1H),7.18(m, 2H), 6.80(br, 1H),6.29(d, J=5.3Hz,1H),5.12(m, 1H), 4.14(m, 2H),3.63(s, 2H), 3.53(m, 4H),2.49(m, 4H),1.57(d,J=7.0Hz, 3H), 1.25(m, 3H) B023 

445.2 CD3OD: 9.62(br, 1H),8.05(d, J=5.3Hz, 1H),7.61(m, 2H), 7.59(s,1H),7.21(m, 2H), 7.05(m, 1H),6.31(d, J=5.3Hz, 1H), 3.78(s,2H), 3.42(m,4H), 3.36(s,2H), 2.21(m, 2H), 1.01(s,9H) B024 

447.2 CD3OD: 9.62(br, 1H),8.05(d, J=5.2Hz, 1H),7.61(m, 3H), 7.21(m,2H),7.15(m, 1H), 6.31(d,J=5.3Hz, 1H), 3.97(s, 2H),3.00(m, 1H),1.27(d,J=6.3Hz, 6H), 1.01(s, 9H) B025 

419.1 CD3OD: 9.42(m, 1H),8.09(d, J=5.1Hz, 1H),7.61(m, 3H), 7.21(m,2H),7.10(m, 1H), 6.35(d,J=5.2Hz, 1H), 3.60(s, 2H),2.30(s, 6H), 1.48(s,9H) B026 

412.0 CD3OD: 9.64(d, J=7.3Hz,1H), 8.21(d, J=5.2Hz, 1H),7.65(m, 5H),7.32(m, 4H),7.05(m, 2H), 6.53(d,J=5.3Hz, 1H), 4.74(s, 2H) B027 

433.1 CD3OD: 9.42(m, 1H),8.09(d, 1H), 7.62(m, 3H),7.21(m, 2H), 7.13(m,1H),6.36(d, 1H), 4.13(s, 2H),3.12(m, 1H), 1.48(s, 9H),1.23(d, 6H) B028 

405.1 CD3OD: 9.63(d, J=7.0Hz,1H), 8.04(d, J=5.2Hz, 1H),7.62(m, 3H),7.20(m, 2H),7.10(m, 1H), 6.30(d,J=5.3Hz, 1H), 4.18(m, 1H),3.62(s, 2H),2.34(s, 6H),1.29(d, J=6.4Hz, 6H) B029 

424.1 CDCl3: 9.60(br, 1H), 8.08(d,J=5.2Hz, 1H), 7.63(m, 2H),7.45(m, 6H),7.11(m, 2H),6.41(d, J=5.4Hz, 1H),5.63(m, 1H), 5.21(m, 1H),2.42(s, 3H),1.63(d, J=7.1Hz,3H) B030 

390.1 CDCl3: 9.42(br, 1H), 8.08(d,J=5.1Hz, 1H), 7.66(m, 2H),7.46(s, 1H),7.14(m, 2H),6.78(m, 1H), 6.42(d,J=5.3Hz, 1H), 5.28(br, 1H),3.38(d,J=6.3Hz, 2H), 2.48(s,3H), 1.06(s, 9H) B031 

417.1 CD3OD: 9.60(d, J=7.0Hz,1H), 8.02(d, J=5.3Hz, 1H),7.61(m, 2H),7.53(s, 1H),7.20(m, 2H), 7.02(m, 1H),6.30(d, J=5.4Hz, 1H),4.17(m, 1H),3.74(s, 2H),3.38(m, 4H), 2.17(m, 2H),1.28(d, J=6.4Hz, 6H) B032 

419.1 CD3OD: 9.61(d, J=7.0Hz,1H), 8.01(d, J=5.3Hz, 1H),7.60(m, 3H),7.20(m, 2H),7.11(m, 1H), 6.28(d,J=5.3Hz, 1H), 4.16(m, 1H),3.90(s, 2H),2.90(m, 1H),1.28(d, J=6.4Hz, 6H), 1.16(d,J=6.2Hz, 6H) B033 

439.1 CD3OD: 9.64(d, J=7.3Hz,1H), 8.21(d, J=5.2Hz, 1H),7.65(m, 5H),7.32(m, 4H),7.05(m, 2H), 6.53(d,J=5.3Hz, 1H), 4.74(s, 2H)

Other EXAMPLES of the invention are shown in the following TABLE 11.These EXAMPLES are made similarly to the compounds and Schemes shownabove.

TABLE 11 EXAMPLE M+1 NMR(CDCl3)

479.4 (d, J=6.9Hz, 3H), 2.2(qn,J=7.0Hz, 2H), 3.3(t, J=7.0Hz,4H), 3.6(s,2H), 5.2(qn J=6.9Hz,1H), 5.8(broad, 1H), 6.4(d,J=5.3Hz, 1H), 6.6(broad,1H),7.1(m, 2H), 7.3(m, 1H), 7.4(m,5H), 7.6(m, 2H), 8.1(d, J=5.2Hz,1H),8.7(broad, 1H).

422.3 1.6(d, J=7.0Hz, 3H), 1.8(broad,4H), 2.6(broad, 4H), 3.7(broad,2H),5.2(qn J=7.0Hz, 1H), 5.6(broad, 1H), 6.4(d, J=5.2Hz,1H), 6.7(broad, 1H),7.1(m, 2H),7.3(m, 1H), 7.4(m, 5H), 7.6(m,2H), 8.1(d, J=5.2Hz, 1H),8.7(broad, 1H).

507.4 1.5(m, 2H), 1.6(d, J=6.9Hz,3H), 1.6–1.8(broad, 4H), 2.4(broad,4H), 3.5(s, 2H), 5.2(qnJ=6.9Hz, 1H), 5.6(broad, 1H),6.4(d, J=5.3Hz, 1H),6.7(broad,1H), 7.1(m, 2H), 7.3(m, 1H), 7.4(m, 4H), 7.6(m, 3H),8.1(d,J=5.3Hz, 1H), 8.7(broad, 1H).

509.4 1.6(d, J=6.9Hz, 3H), 2.5(m,4H), 3.6(s, 2H), 3.8(m, 4H), 5.2(qnJ=6.9Hz, 1H), 5.8(broad,1H), 6.4(d, J=5.2Hz, 1H), 6.7(broad, 1H), 7.1(m,2H), 7.3(m,1H), 7.4(m, 4H), 7.6(m, 3H), 8.1(d, J=5.2Hz, 1H),8.7(broad,1H).

555.4 1.6(d, J=7.1Hz, 3H), 2.8(d,J=5.7Hz, 4H), 3.4(s, 6H),3.5(t,J=5.8Hz, 4H), 3.8(s, 2H), 5.2(qn J=7.0Hz, 1H), 5.7(broad,1H),6.4(d, J=5.3Hz, 1H), 6.7(broad, 1H), 7.1(m, 2H), 7.3(m,1H), 7.4(m, 4H),7.6(m, 3H), 8.1(d, J=5.3Hz, 1H), 8.7(broad,1H).

525.4 1.6(d, J=6.9Hz, 3H), 2.4(s, 3H),3.4(s, 2H), 3.8(m, 5H),5.2(qnJ=6.8Hz, 1H), 5.8(broad, 1H),6.4(d, J=5.2Hz, 1H), 6.7(broad,1H),7.1(m, 2H), 7.3(m, 1H), 7.4(m, 4H), 7.6(m, 3H), 8.1(d,J=5.2Hz, 1H),8.7(broad, 1H).

497.4 2.2(s, 3H), 2.7(2.7, 2H), 3.4(s,3H), 3.6(t, J=5.7Hz, 2H),3.7(s,2H), 4.8(d, J=5.9Hz, 2H), 5.8(broad, 1H), 6.5(d, J=5.3Hz,1H),6.8(broad, 1H), 7.1(m, 2H),7.4(m, 5H), 7.6(m, 3H), 8.1(d,J=5.2Hz, 1H),9.1(broad, 1H).

481.5 1.1(broad, 6H), 2.6(broad, 4H),3.6(s, 2H), 4.8(d, J=5.9Hz,2H),5.8(broad, 1H), 6.5(d, J=5.3Hz,1H), 6.8(broad, 1H), 7.1(m,2H),7.3(m, 1H), 7.4(m, 4H), 7.6(m,3H), 8.1(d, J=5.2Hz, 1H), 9.1(broad,1H).

495.4 1.0(t, J=7.2Hz, 3H), 1.6(m, 2H),1.6(d, J=6.8Hz, 3H), 2.2(s,3H),4.4(t, J=7.2Hz, 2H), 3.6(s, 2H),5.2(qn J=6.8Hz, 1H), 5.8(broad,1H),6.4(d, J=5.3Hz, 1H), 6.7(broad, 1H), 7.1(m, 2H), 7.3(m,1H), 7.4(m, 5H),7.6(m, 2H), 8.1(d, J=5.3Hz, 1H), 8.7(broad,1H).

524.4 1.6(d, J=7.0Hz, 3H), 2.29(s,2H), 2.33(s, 3H), 2.6(m, 4H), 3.6(s,2H), 5.2(qn J=7.0Hz, 1H),5.6(d, J=6.4Hz, 1H), 6.4(d,J=5.3Hz, 1H),6.7(broad, 1H),7.1(m, 2H), 7.3(m, 1H), 7.4(m,5H), 7.6(m, 2H), 8.1(d,J=5.3Hz,1H), 8.7(broad, 1H).

945.8

538.4 1.6(d, J=6.8Hz, 3H), 2.4(s, 3H),3.0(s, 3H), 3.1(s, 3H), 3.3(s,2H),3.7(s, 2H), 5.2(qn J=6.8Hz,1H), 5.8(broad, 1H), 6.4(d,J=5.4Hz, 1H),6.7(broad, 1H),7.1(m, 2H), 7.3(m, 1H), 7.4(m,4H), 7.6(m, 3H), 8.1(d,J=5.3Hz,1H), 8.7(broad, 1H).

1.6(d, J=6.9Hz, 3H), 3.4(s, 2H),5.2(qn J=6.9Hz, 1H), 5.6(broad,1H),6.4(d, J=5.3Hz, 1H), 6.6(broad, 1H), 7.1(m, 2H), 7.3(m,1H), 7.4(m, 4H),7.6(m, 3H), 8.1(d, J=5.3Hz, 1H), 8.7(broad,1H).

566.2 1.0(m, 6H), 1.6(d, J=6.9Hz,3H), 2.4(s, 3H), 3.3(s 2H), 3.4(m, 4H),3.7(s, 2H), 5.2(qn J=6.9Hz, 1H), 5.7(broad, 1H), 6.4(d,J=5.2Hz, 1H),6.7(broad, 1H),7.1(m, 2H), 7.3(m, 1H), 7.4(m,4H), 7.6(m, 3H), 8.1(d,J=5.2Hz, 1H), 8.7(broad, 1H).

552.2 1.1(m, 3H), 1.6(d, J=6.9Hz,3H), 2.4(2s, 3H), 2.9 & 3.1(2s2H),3.3(2s, 2H), 3.5(m, 2H), 3.7(m, 2H), 5.2(qn J=6.7Hz, 1H),5.7(broad, 1H),6.4(d, J=5.2Hz,1H), 6.7(broad, 1H), 7.1(m, 2H),7.3(m, 1H), 7.4(m, 4H),7.6(m,3H), 8.1(d, J=5.2Hz, 1H),8.7(broad, 1H).

524.1 1.6(d, J=6.8Hz, 3H), 2.4(s, 3H),2.9(d, J=5.1Hz, 2H), 3.1(s,3H),3.7(s, 2H), 5.2(qn J=6.9Hz,1H), 5.7(broad, 1H), 6.4(d,J=5.3Hz, 1H),6.5(broad, 1H),7.1(m, 3H), 7.3(m, 1H), 7.4(m,4H), 7.6(m, 3H), 8.1(d,J=5.3Hz, 1H), 8.7(broad, 1H).

536.2 1.6(d, J=6.8Hz, 3H), 2.2(m,2H), 2.5(m, 1H), 2.8(d, J=5.1Hz,3H),3.5(m, 1H), 3.6(m,1H), 3.8(m, 2H), 5.2(qn J=6.9Hz,1H), 5.7(broad, 1H),6.4(d,J=5.2Hz, 1H), 6.5(broad, 1H),7.1(m, 3H), 7.3(m, 1H), 7.4(m,4H),7.6(m, 3H), 8.1(d, J=5.2Hz, 1H), 8.7(broad, 1H).

419.2 1.01(s, 9h), 2.46(s, 3H), 3.34(s,2H), 3.87(s, 2H), 6.32(d,J=5.3Hz, iH), 7.11(m, 1H), 7.21(m,2H), 7.60(m, 3H), 8.05(d, J=5.3Hz,2H), 9.62(br, 1H),

550.2 1.6(d, J=6.8Hz, 3H), 2.3(m,2H), 2.8(m, 7H), 3.4(m, 1H), 3.5(m,1H), 4.0(m, 2H), 5.2(qnJ=7.0Hz, 1H), 5.7(broad, 1H),6.4(d, J=5.3Hz, 1H),6.5(broad,1H), 7.1(m, 3H), 7.3(m, 1H), 7.4(m, 5H), 7.6(m, 2H),8.1(d,J=5.3Hz, 1H), 8.8(broad, 1H). ES+ Ex. STRUCTURE (M+1) D01

494.1 D02

406.2 D03

456.2 D04

494.2 D05

483.3 D06

416.1(ES−) D07

454.3 D08

592.3 D09

440.3 D10

470.2 D11

433.3 D12

478.2 D13

444.2 D14

404.2 D15

444.2 D16

440.2 D17

460.3 D18

420.3 D19

486.2 D20

456.2 D21

510.2 D22

456.2 D23

486.2 D24

462.3 D25

476.3 D26

486.2 D27

454.3 D28

462.3 D29

472.2 D30

486.2 D31

376.3 D32

378.2 D33

406.3 D34

438.6(ES−) D35

444.3 D36

392.3 D37

406.3 D38

364.3 D39

378.3 D40

406.3 D41

392.3 D42

454.3 D43

468.3 D44

408.3 D45

394.3 D46

380.3 D47

390.3 D48

394.3 D49

349.2 D50

408.3 D51

406.3 D52

462.3 D53

471.3 D54

483.3 D55

467.3 D56

471.3 D57

505.3 D58

513.3 D59

513.4 D60

499.3 D61

497.4 D62

467.4 D63

431.4 D64

487.3 D65

509.4 D66

363.5 D67

417.9(ES−) D68

405.9 D69

405.7 D70

517.6 D71

453.8 D72

446.7 D73

567.7 D74

553.7 D75

537.8 D76

538.4 D77

551.7 D78

466.7 D79

390.7 D80

404.7 D81

432.8 D82

432.6 D83

402.7 D84

418.7 D85

512.7 D86

494.7 D87

432.7 D88

432.7 D89

434.6 D90

416.7 D91

420.7 D92

435.7 D93

488.6 D94

488.6 D95

480.7 D96

433.7 D97

447.7 D98

475.7 D99

523.7 D100

537.7 D101

459.9 D102

475.7 D103

418.0(ES−) D104

406.5 D105

420.5 D106

452.2(ES−) D107

420.5 D108

390.4 D109

405.4 D110

419.0(ES−) D111

401.4 D112

407.4 D113

387.4 D114

407.4 D115

402.4 D116

432.5 D117

420.4 D118

459.3ES −0 D119

463.5 D120

475.3(ES−) D121

457.5 D122

458.5 D123

488.5 D124

476.5 D125

405.1 D126

363   D127

475.8 D128

473.7 D129

531.8 D130

529.9 D131

478.8 D132

432.8 D133

447.8 D134

418.8 D135

461.8 D136

432.8 D137

432.8 D138

512.9 D139

446.8 D140

416.8 D141

431.7 D142

443.7 D143

479.7 D144

457.8 D145

443.7 D146

460.7 D147

471.7 D148

465.7 D149

440.6 D150

446.7 D151

430.7 D152

482.7 D153

415.8

EXAMPLE E1 to EXAMPLE E192 below were made by procedures similar tothose described above.

EX. E1

EX. E2

EX. E3

EX. E4

EX. E5

EX. E6

EX. E7

EX. E8

EX. E9

EX. E10

EX. E11

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EX. E13

EX. E14

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EX. E16

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EX. E20

EX. E21

EX. E22

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EX. E25

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EX. E27

EX. E28

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EX. E31

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EX. E34

EX. E35

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EX. E37

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EX. E39

EX. E40

EX. E41

EX. E42

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EX. E48

EX. E49

EX. E50

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EX. E64

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EX. E85

EX. E86

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EX. E88

EX. E89

EX. E90

EX. E91

EX. E92

EX. E93

EX. E94

EX. E95

EX. E96

EX. E97

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EX. E99

EX. E100

EX. E101

EX. E102

EX. E103

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EX. E109

EX. E110

EX. E111

EX. E112

EX. E113

EX. E114

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EX. E116

EX. E117

EX. E118

EX. E119

EX. E120

EX. E121

EX. E122

EX. E123

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EX. E126

EX. E127

EX. E128

EX. E129

EX. E130

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EX. E133

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EX. E136

EX. E137

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EX. E140

EX. E141

EX. E142

EX. E143

EX. E144

EX. E145

EX. E146

EX. E147

EX. E148

EX. E149

EX. E150

EX. E151

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EX. E153

EX. E154

EX. E155

EX. E156

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EX. E158

EX. E159

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EX. E162

EX. E163

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EX. E165

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EX. E167

EX. E168

EX. E169

EX. E170

EX. E171

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EX. E174

EX. E175

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EX. E177

EX. E178

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EX. E180

EX. E181

EX. E182

EX. E183

EX. E184

EX. E185

EX. E186

EX. E187

EX. E188

EX. E189

EX. E190

EX. E191

EX. E192

EXAMPLE F1 to EXAMPLE F182 below were made by procedures similar tothose described above.

EX. F1

EX. F2

EX. F3

EX. F4

EX. F5

EX. F6

EX. F7

EX. F8

EX. F9

EX. F10

EX. F11

EX. F12

EX. F13

EX. F14

EX. F15

EX. F16

EX. F17

EX. F18

EX. F19

EX. F20

EX. F21

EX. F22

EX. F23

EX. F24

EX. F25

EX. F26

EX. F27

EX. F28

EX. F29

EX. F29

EX. F30

EX. F31

EX. F32

EX. F33

EX. F34

EX. F35

EX. F36

EX. F37

EX. F38

EX. F39

EX. F40

EX. F41

EX. F42

EX. F43

EX. F44

EX. F45

EX. F46

EX. F47

EX. F48

EX. F49

EX. F50

EX. F51

EX. F52

EX. F53

EX. F54

EX. F55

EX. F56

EX. F57

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EX. F60

EX. F61

EX. F62

EX. F63

EX. F64

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EX. F66

EX. F67

EX. F68

EX. F69

EX. F70

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EX. F72

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EX. F75

EX. F78

EX. F79

EX. F80

EX. F81

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EX. F83

EX. F84

EX. F85

EX. F86

EX. F87

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EX. F89

EX. F90

EX. F91

EX. F92

EX. F93

EX. F94

EX. F95

EX. F96

EX. F97

EX. F98

EX. F99

EX. F100

EX. F101

EX. F102

EX. F103

EX. F104

EX. F105

EX. F106

EX. F107

EX. F108

EX. F109

EX. F110

EX. F111

EX. F112

EX. F113

EX. F114

EX. F115

EX. F116

EX. F117

EX. F118

EX. F119

EX. F120

EX. F121

EX. F122

EX. F123

EX. F124

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EX. F126

EX. F127

EX. F128

EX. F129

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EX. F131

EX. F132

EX. F133

EX. F134

EX. F135

EX. F136

EX. F137

EX. F138

EX. F139

EX. F140

EX. F141

EX. F142

EX. F143

EX. F144

EX. F145

EX. F146

EX. F147

EX. F148

EX. F149

EX. F150

EX. F151

EX. F152

EX. F153

EX. F154

EX. F155

EX. F156

EX. F157

EX. F158

EX. F159

EX. F160

EX. F161

EX. F162

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EX. F165

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EX. F167

EX. F168

EX. F169

EX. F170

EX. F171

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EX. F173

EX. F174

EX. F175

EX. F176

EX. F177

EX. F178

EX. F179

EX. F180

EX. F181

EX. F182

1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof, wherein FusedHet is

R¹ is H, —C₁₋₆alkyl, —C(O)(C₁₋₆alkyl), —C(O)—C₁ ₆alkyl-aryl,—C₀₋₄alkyl-aryl, —C₀₋₄alkyl-indanyl, C₀₋₄alkyl-imidazolyl,—C₀₋₄alkyl-thiazolyl, —C₀₋₄alkyl-pyrazolyl, —C₀₋₄alkyl-oxadiazolyl, —C₀₄alkyl-C₃ ₆cycloalkyl, —C₀₋₄alkyl-C₁ ₄alkoxy,—C₁₋₄alkyl-N(C₀₋₄alkyl)(—C₀₋₄alkyl),—C₁₋₄alkyl-N(—C₀₋₄alkyl)—CO—C₁₋₄alkoxy, C₁₋₄alkyl-piperadinyl,—C₀₋₄alkyl-triazolyl, —C₁₋₄alkyl-imidazothiazolyl, —C₁₄alkyl-benzimidazolyl, —C₁₋₄alkyl-benzothiazolyl,—C₁₋₄alkyl-benzotetrahydrofuranyl, C₁₋₄alkyl-benzodioxolyl, —C₁₄alkyl-(heterocycloC₄O₂alkyl), —C₁₋₄alkyl-(heterocycloC₅O₁alkyl),—C₁₋₄alkyl-tetrahydrofuran, or —C₁₋₄alkyl-oxetanyl; R¹¹ is H orC₁₋₆alkyl; or R¹ and R¹¹, together with the N to which they areattached, form a morpholinyl; R², R²¹, R²² each independently is H,halogen, or —C₁₋₄alkyl; R³ is H, —C₁₋₄alkyl, —C₃₋₆cycloalkyl,—C₁₋₄alkyl-aryl, —C₁₋₄alkyl-azetidinyl,—C₁₋₄alkyl-azetidinyl-CO—C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),—C₁₋₄alkyl-pyrrolidinyl, —C₁ ₄alkyl-piperidinyl, —C₁₋₄alkyl-morpholinyl,—C₁₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),—C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl-C₁₋₄alkoxy),—C₀₋₄alkyl-N(C₀₋₄alkyl-C₁₋₄alkoxy)(C₀₋₄alkyl-C₁₋₄alkoxy),—C₁₋₄alkyl-N(C₀₋₄alkyl)—(C₁₋₄alkyl)-aryl,—C₁₋₄alkyl-N(C₀₋₄alkyl)—C₁₋₄alkyl-tetrahydrofuranyl,—C₁₋₄alkyl-N(C₀₋₄alkyl)—C₁₋₄alkyl-azetidinyl,—C₁₋₄alkyl-N(C₀₋₄alkyl)—C₁₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),—C₁₋₄alkyl-N(C₀₋₄alkyl)—C₁₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-SO₂C₁₋₄alkyl),—CO—N(C₀₋₄alkyl)—C₁₋₄alkyl-aryl, CON(C₀₋₄alkyl)—C₁₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl), —C₀₋₄alkyl-CO—C₀₋₄alkyl,—C₀₋₄alkyl-CO—C₀₋₄alkoxy,—C₀₋₄alkyl-CO—N(C₀₋₄alkyl)—C₁₋₄alkyl-C₁₋₄alkoxy,—C₀₋₄alkyl-CO—N(C₀₋₄alkyl)—C₁₋₄alkyl-aryl, —C₀₋₄alkyl-CO-piperidinyl,—C₁₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),C₀₋₄alkyl-CO—C₀₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl), O C₁₋₄alkyl-aryl,C₁₋₄alkyl O C₁₋₄alkyl, —C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl,—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkoxy, —C₀₋₄alkyl-N(C₀₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-aryl, —C₀₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl(aryl)₂,—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-pyrrolyl,—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-pyrrolidinyl,—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₀₋₄alkyl-azetidinyl,—C₀₋₄alkyl-N(C₀₋₄alkyl) C₀₋₄alkyl-CO—C₂₋₄alkenyl-pyrrolidinyl,—C₀₋₄alkyl-N(C₀₋₄alkyl) C₀₋₄alkyl-CO C₀₋₄alkyl thiophenyl,—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₂₋₄alkenyl-thiophenyl,—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—S—C₁₋₄alkyl-aryl,—C₀₋₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—C₃₋₆cyclolkyl, —C₀₄alkyl-N(C₀₋₄alkyl)—C₀₋₄alkyl-CO—O—C₁₋₄alkyl-aryl,—C₀₋₄alkyl-CO—N(C₀₋₄alkyl)—C₀₋₄alkyl-C₁₋₄alkoxy,—C₁₋₄alkyl-N(C₀₋₄alkyl)(—SO₂C₁₋₄alkyl),C₀₋₄alkyl-N(C₀₋₄alkyl)—C₁₋₄alkyl-SO₂C₁₋₄alkyl,—C₀₋₄alkyl-S—C₁₋₄alkyl-aryl, —C₁₋₄alkyl-PO(C₁₋₄alkoxy)(C₁₋₄alkoxy),—C₁₋₄alkyl-azetidinyl-CO—N(C₀₋₄alkyl)(C₀₋₄alkyl),—C₁₋₄alkyl-(heterocycloC₄N₁O₁alkyl), —C₀₄alkyl-CO—(heterocycloC₅N₁alkyl),—C₀₋₄alkyl-CO—N(C₀₋₄alkyl)-(heterocycloC₅N₁alkyl),—C₁₋₄alkyl-(heterocycloC₄N₂alkyl)—C₁₋₄alkyl,C₁₋₄alkyl-(heterocycloC₄N₂alkyl)—CO—C₀₋₄alkoxy,—C₁₋₄alkyl-(heterocycloC₄N₂alkyl)—C₁₋₄alkyl-N(C₀₋₄alkyl)(C₀₋₄alkyl),—C₁₋₄alkyl-(heterobicycloC₅N₂alkyl)—C₁₋₄alkyl, or—C₁₋₄alkyl-NH-(heterobicycloC₇N₁alkyl); and R⁴ is —C₁₋₆alkyl; whereinany of the above aryl, hetaryl, cycloalkyl, or heterocycloalkyloptionally is substituted with 1–4 substituents, each substituentindependently is halogen, NO₂, —CN, —C₁₋₄alkyl, —C₀₋₄alkoxy, SC₁₋₄alkyl, or C₀₋₄alkyl-(CO)—C₀₋₄alkoxy: and any of the above alkyloptionally is substituted with 1–4 substituents, each substituentindependently is halogen, —N₃, —CN, —COOH, or —C₀₋₄alkoxy.
 2. Thecompound according to claim 1, wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.
 3. The compoundaccording to claim 1, wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.
 4. The compoundaccording to claim 1, wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.
 5. The compoundaccording to claim 1, wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.
 6. The compoundaccording to claim 1, wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.
 7. The compoundaccording to claim 1, wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.
 8. The compoundaccording to claim 1, wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.
 9. The compoundaccording to claim 1, wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.
 10. The compoundaccording to claim 1 represented by

or a pharmaceutically acceptable salt thereof.
 11. The compoundaccording to claim 1 represented by:

wherein Ar, R, and Z are Ar Group R Group Z Group 2,4-DifluorophenylNHCH₂C(CH₃)₃ CH₂OH 2,4-Difluorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂2,4-Difluorophenyl

CH₂OH 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl NHCH₂C(CH₃)₃ CH₂OCH₃3-Trifluoromethylphenyl NHCH₂C(CH₃)₃

3-Trifluoromethylphenyl NHCH₂C(CH₃)₃

3-Trifluoromethylphenyl NHCH₂C(CH₃)₃

3-Trifluoromethylphenyl NHCH₂C(CH₃)₃ CH₂OH 3-TrifluoromethylphenylNHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 2-Chloro-4-fluorophenyl NHCH₂C(CH₃)₃ CH₂OH2-Chloro-4-fluorophenyl NHCH₂C(CH₃)₃ CHO 2-Chloro-4-fluorophenylNHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 2-Chlorophenyl NHCH₂C(CH₃)₃ CH₂OH 2-ChlorophenylNHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 4-Chlorophenyl NHCH₂C(CH₃)₃ CH₂OH 4-ChlorophenylNHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 3,4-Dichlorophenyl NHCH₂C(CH₃)₃ CH₂OH3,4-Dichlorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 2,3-DichlorophenylNHCH₂C(CH₃)₃ CH₂OH 2,3-Dichlorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂4-Fluorophenyl NHCH₂C(CH₃)₃ H 4-Fluorophenyl NHCH₂C(CH₃)₂CH₂OH H4-Fluorophenyl NHCH₂C(CH₃)₂CH₂OH CH₂NHCH₃ 4-FluorophenylNHCH₂C(CH₃)₂CH₂OH CH₂N(CH₃)SO₂CH₃ 4-Fluorophenyl

CH₃ 4-Fluorophenyl NHCH₂C(CH₃)₃ CH₂NHSO₂CH₃ 4-Fluorophenyl NHCH₂C(CH₃)₃CH₂N(CH₃)SO₂CH₃ 4-Fluorophenyl NHCH₂C(CH₃)₃ CH₂PO(OMe)₂ 4-FluorophenylNHCH₂C(CH₃)₃ CH₂SO₂CH₃ 4-Fluorophenyl NHCH₂C(CH₃)₃ CHO

or a pharmaceutically acceptable salt thereof.
 12. The compoundaccording to claim 1 represented by:

wherein Ar and R are: Ar Group R Group 2,4-Difluorophenyl NHCH₂C(CH₃)₃3-Trifluoromethylphenyl NHCH₂C(CH₃)₃ 3-Trifluoromethylphenyl

3-Trifluoromethylphenyl NH(CH₂)₃OCH₃ 4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl NHCH₂C(CH₃)₂CH₂OH 4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl NH(CH₂)₃OCH₃ 4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 1 represented by: R Group Z Group NHCH₂C(CH₃)₃CON(OMe)Me NHCH₂C(CH₃)₃ CHO NHCH₂C(CH₃)₃ CH₂OH NHCH₂C(CH₃)₃ CH₂N(CH₃)₂

CON(OMe)Me

CHO

CH₂OH

CH₂N(CH₃)₂

or a pharmaceutically acceptable salt thereof.
 14. The compoundaccording to claim 1 represented by:

wherein Ar, R, and Z are Ar Group R Group Z Group 4-FluorophenylNHCH₂C(CH₃)₃ CH₂OH 4-Fluorophenyl NHCH₂C(CH₃)₃ CON(OMe)Me3-Trifluoromethylphenyl NHCH₂C(CH₃)₃ CON(OMe)Me 3-TrifluoromethylphenylNHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 2-Chlorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂2-Chloro-4-fluorophenyl NHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 2,4-DifluorophenylNHCH₂C(CH₃)₃ CH₂N(CH₃)₂ 2,4-Difluorophenyl NHCH₂C(CH₃)₃ CH₂OH2,4-Difluorophenyl NHCH₂C(CH₃)₃ CON(OMe)Me 2,4-DifluorophenylNHCH₂C(CH₃)₃

2,4-Difluorophenyl NHCH₂C(CH₃)₃

2,4-Difluorophenyl NHCH₂C(CH₃)₃

2,4-Difluorophenyl NHCH₂C(CH₃)₃

2,4-Difluorophenyl NHCH₂C(CH₃)₃

2,4-Difluorophenyl NHCH₂C(CH₃)₃ CH₂NH(CH₂)₂OCH₃ 2,4-DifluorophenylNHCH₂C(CH₃)₃ CH₂NH(CH₂)₂N(CH₃)₂ 2,4-Difluorophenyl NH(CH₂)₃OCH₃CON(OMe)Me 2,4-Difluorophenyl

CON(OMe)Me 2,4-Difluorophenyl

CON(OMe)Me 2,4-Difluorophenyl NHCH₂C(CH₃)₂CH₂OH CH₂OH 2,4-Difluorophenyl

CON(OMe)Me 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

2,4-Difluorophenyl

2,4-Difluorophenyl NHCH₂C(CH₃)₂CH₂OH CH₂N(CH₃)₂ 2,4-DifluorophenylNH(CH₂)₃OCH₃

2,4-Difluorophenyl NH(CH₂)₃OCH₃ CH₂N(CH₃)₂ 2,4-DifluorophenylNHCH₂C(CH₃)₂CH₂OH CON(OMe)Me 2,4-Difluorophenyl NH(CH₂)₄OH CH₂N(CH₃)₂2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl

CH₂N(CH₃)₂ 2,4-Difluorophenyl NH(CH₂)₃CO₂H CH₂N(CH₃)₂

or a pharmaceutically acceptable salt thereof.
 15. The compoundaccording to claim 1 represented by

wherein R is R

or a pharmaceutically acceptable salt thereof.
 16. The compoundaccording to claim 1 represented by

wherein R is R

or a pharmaceutically acceptable salt thereof.
 17. The compoundaccording to claim 1 represented by

wherein R is R

or a pharmaceutically acceptable salt thereof.
 18. The compoundaccording to claim 1 represented by

wherein R is R

or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 1 represented by

or a pharmaceutically acceptable salt thereof.
 20. The compoundaccording to claim 1 represented by

or a pharmaceutically acceptable salt thereof.
 21. The compoundaccording to claim 1 represented by

or a pharmaceutically acceptable salt thereof.
 22. A compoundrepresented by

or a pharmaceutically acceptable salt thereof.
 23. A compoundrepresented by

or a pharmaceutically acceptable salt thereof.
 24. A pharmaceuticalcomposition comprised of a compound in accordance with claim 1 incombination with a pharmaceutically acceptable carrier.
 25. A method oftreating a cytokine mediated disease in a mammal, comprising:administering to a mammalian patient in need of such treatment acompound as described in claim 1 in an amount which is effective totreat said rheumatoid arthritis.